headsUPmigraine highly recommends this 2018 paper by researchers KC Brennan and Daniela Pietrobon. Because the paper includes extended, technical discussions of brain chemistry, we’ve excerpted passages most likely to be of interest to people with migraine and advocates. If you’d like to read the full paper, find it here. Bold type within paragraphs is added.

a

A Systems Neuroscience Approach to Migraine

⏩ K.C. Brennan and Daniela Pietrobon (Neuron 2018)

Migraine is an extremely common but poorly understood

nervous system disorder. We conceptualize migraine as a

disorder of sensory network gain and plasticity, and we

propose that this framing makes it amenable to the tools

of current systems neuroscience.

⏩ Considering Migraine as a Systems Neuroscience Problem

Two characteristics of migraine make it a very interesting

systems neuroscience problem. First, the migraine attack is

not only an anatomically specific pain state, but also (at least

phenotypically) a paroxysmal disorder of pan-sensory gain.

Second, the transition from acute to chronic migraine appears

to represent a multisite, dysfunctional plasticity of sensory,

autonomic, and affective circuits.

In order to understand the migraine attack from a systems

neuroscience perspective, we need to understand how a sensory

and autonomic network can switch, within a few minutes,

from a state of relative equilibrium to one in which there is both

spontaneous pain and amplification of percepts from multiple

senses. We also need to understand how the sensory changes

that occur in a migraine attack become a near-constant experience

in chronic migraine.

Because migraine is a whole nervous system disease, any

attempt to summarize it entirely can be daunting. Though we

refer to the clinical migraine literature as a reference point, our

primary focus is on how the disease (in particular the migraine

attack and chronic migraine) can be approached mechanistically

in animal model systems. Our overall goal is to increase awareness

of this understudied disease in the neuroscientific community

by trying to view it through the lens of modern systems

neuroscience.

⏩ Characteristics of Migraine

Migraine affects 12% of the world’s population (Jensen and

Stovner, 2008; Lipton et al., 2007). It is commonly thought of

as a disorder of episodic, severe headache, but this understates

both its pathophysiological complexity and its human

impact. Migraine attacks are often incapacitating, and they primarily

affect people in their working and child-rearing years.

Chronic migraine (migraine more than 15 days of the month)

affects 2% of the world’s population (May and Schulte,

2016). The economic costs of migraine, driven mainly by

chronic migraine, range between $20 and $30 billion a year in

the United States (Stewart et al., 2003). The true societal costs

of this stigmatized, poorly understood disease are hard to

calculate.

Migraine is a disorder primarily affecting the sensory nervous

system (Pietrobon and Moskowitz, 2013). It is punctuated by attacks

that generally last a few hours and include a throbbing,

unilateral head pain that can range from mild to excruciating. However,

the headache is only one element of a larger whole. In addition

to head pain, there is often pain in the neck and shoulders.

Nausea and vomiting, representing interoception and autonomic

outflow from the gut, are prominent features. There can also be

autonomic phenomena in the face, typically reddening of the

eyes, tearing, flushing, or pallor (Goadsby et al., 2002). Finally,

the majority of migraine attacks feature sensory amplifications:

photophobia, phonophobia, osmophobia, and cutaneous allodynia—

the perception of light, sound, smell, and normal touch as

amplified or painful (Burstein et al., 2015). Thus, the migraine

attack is not so much a simple headache as it is a paroxysmal alteration

in gain, or input-output modulation (Haider andMcCormick,

2009), of multiple sensory systems (Figure 1).

The migraine attack is the most visible element of a larger

disease continuum. In up to a third of patients, the attack is heralded

by an aura; this is a typically sensory hallucination, with

visual or somatic percepts that do not exist in the environment.

It can also affect speech function, indistinguishably from the

aphasia seen in stroke, except that it is reversible. Up to 72 hr

before an attack, some patients experience premonitory symptoms—

cognitive changes, hunger/thirst, euphoria, or irritability.

Following the attack, sensory function typically does not immediately

return to normal; milder pain and sensory amplifications

can persist for hours to days (Goadsby et al., 2002; Olesen

et al., 2013).

Between attacks, there are alterations in sensory physiology

that appear to vary in time with the attack profile, suggesting an

underlying cyclicity in sensory gain that culminates in the attack

(de Tommaso et al., 2014). One of the most important problems

in clinical migraine is the progression from an intermittent,

self-limited inconvenience to a life-changing disorder of chronic

pain, sensory amplification, and autonomic and affective disruption.

This progression, sometimes termed chronification in the

migraine literature, is common, affecting 3% of migraineurs in a

given year, such that 8% of migraineurs have chronic migraine

in any given year (May and Schulte, 2016). The chronification process

results in a persistent alteration in the way the sensory

network responds to the environment; that is, at least phenomenologically

a dysfunctional plasticity of the sensory network.

⏩ Migraine Chronification as a Progressive Sensory Dysplasticity

Along with understanding how the migraine attack starts, understanding

how episodic migraine becomes chronic is one of

the most important challenges in migraine neuroscience. The

majority of the clinical, financial, and emotional burden of

migraine is from chronic migraine (May and Schulte, 2016). There

is also psychophysical and physiological evidence that sensory

processing is altered in chronic migraine. For example, cutaneous

allodynia is more common as disease duration increases(Lipton et al.,

2008) and indeed is associated with chronification

(Louter et al., 2013). Visually evoked magnetoencephalographic

potentials show higher amplitudes in chronic migraine (Chen

et al., 2011b) and return to sizes seen in episodic migraine

when patients are effectively treated (Chen et al., 2012).

From the neuroscientific perspective, understanding how an

episodic neurologic disorder becomes chronic (and remits)

could offer deep insights into sensory learning and plasticity as

well as pain progression. . . . Importantly, these

changes in sensory response persist after the migraine-relevant

stimulus has stopped, suggesting that a persistent sensitization

has been entrained.

⏩ An Integrative View: Making Sense of Multisensory Gain from

    a Network Perspective

The above section touched on locations that are likely relevant

to the migraine attack and chronification. But how are they bound?

What are the potential circuit substrates of pan-sensory amplification

in migraine?

Both the migraine attack and the chronic migraine state are

intrinsically multisensory, involving vision (photophobia), somatosensation

(allodynia), audition (phonophobia), olfaction (osmophobia),

and interoception (head pain and nausea). Such broad,

temporally synchronous sensory amplification, presumably

occurring in diverse brain regions, is difficult to explain in the

absence of coordinated activity. We hypothesize that migraine

must take advantage of preexisting circuit mechanisms that

bind and amplify multiple sensory modalities. These mechanisms

must be capable of increasing the gain of the sensory

response over potentially all modalities within tens of minutes.

 ⏩ The Migraine Attack

It may be useful to work backward, considering a hypothetical

scenario where a migraine attack with all its sensory amplifications

is entrained. In this scenario, we posit that pyramidal

neurons in the visual, somatosensory, auditory, olfactory, and

insular cortex (among others) experience an increase in the

slope of their input-output function (or an increase in gain;

Figure 1; Haider and McCormick, 2009). How might this occur,

within a tens-of-minutes time frame and persist for the duration

of the attack? Multiple, potentially summating mechanisms

could contribute. … This could be envisioned as a ‘‘daisy chain’’

process (Sandkuhler and Gruber-Schoffnegger, 2012), whereby

one activated region triggers another region, or one that is

coordinated by hub regions (e.g., thalamus, insula, anterior

cingulate, amygdala, and hypothalamus). …

[T]he earliest changes associated with the migraine attack occur

in the TNC, rostral dorsal pons (an area which contains LC, nucleus

cuneiformis, and PBN), and hypothalamus. During the attack

proper, when sensory amplifications are present, activation is

consistently seen in the rostral dorsal pons, thalamus, insula,

anterior cingulate, sensory cortex, and temporal pole/amygdala.

Importantly, the response to diverse sensory stimuli (brush,

painful heat, visual checkerboard, and ammonia inhalation) is

increased in multiple sensory cortices (somatosensory, insula,

visual, auditory, secondary sensory, and visual) during the attack

(Maniyar et al., 2014; Schulte and May, 2016; Schwedt et al.,

2015; Sprenger and Borsook, 2012).

Nociceptive and pan-sensory circuit activation is almost surely

not linear or one way. Feed-forward and feedback gain modulation

through cortico-cortical and corticofugal output could perpetuate

and amplify salience network activation and thus pansensory

gain. … The migraine attack appears necessarily to be a coordinate,

whole-nervous-system event.

⏩ Transition to Chronic Migraine

Long-lasting and/or repetitive pain over years leads to profound

functional as well as structural changes in the brain networks,

reflecting maladaptive plasticity at several levels of the neuraxis

and especially the cortex (Tracey and Mantyh, 2007). Reorganization

of brain circuitry as a consequence of repeated Migraine attacks

is suggested by correlations between functional imaging abnormalities in

chronic-pain-relevant regions and either the number of migraine attacks

or the number of years with migraine  (Schwedt et al., 2015; Sprenger and

Borsook, 2012). Interestingly, in chronic migraineurs, electrophysiological

changes in sensory cortices are similar to those in episodic migraineurs

during migraine attacks; thus, from an electrophysiological point of view,

chronic migraine indeed resembles a never-ending migraine attack 

(Coppola and Schoenen, 2012). This is consistent with the idea that the

transition from episodic to chronic migraine may involve a shift from the transient

sensory amplifications of the migraine attack to a persistent state of sensitization

and sensory amplification.

⏩ Questions for Further Research

The central argument of this article is that the migraine attack

and chronic migraine can be usefully understood as disruptions

in sensory gain and plasticity. …

It is a near-complete mystery how a migraine attack starts. For

attacks that begin with migraine aura, how can such a massive

depolarization arise from apparently normal brain? For migraine

without aura, what changes in network function allow the initiation

of a perpetuated pain process? How does a migraine attack

stop? On longer timescales, how does episodic migraine become chronic? …

Migraine research was once described by an NIH leader as

‘‘primitive.’’ This is not inaccurate, although it is also fair to characterize

migraine neuroscience as a field in its infancy, with

tremendous opportunity. It is a disease that is being increasingly

recognized by society as significant and worthy of investigation,

and it could benefit immensely from the skills of trained neuroscientists.

FULL TEXT including illustrations and bibliography: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402597/

 headsUPmigraine (Twitter & Facebook)

Directors @JillPiggott, PhD, & @NitaGhei, PhD, JD