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Migraine understood as a sensory threshold disease

Peng, Kuan-Poa,b; May, Arnea,*

doi: 10.1097/j.pain.0000000000001531
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Migraine encompasses a broader spectrum of sensory symptoms than just headache. These “other” symptoms, eg, sensory phobias, cognitive and mood changes, allodynia, and many others indicate an altered sensitivity to sensory input which can be measured, in principle, by quantifying sensory threshold changes longitudinally over time. Photophobia, for example, can be quantified by investigating the discomfort thresholds towards the luminance of light. The aim of this review is to look into how thresholds change in patients with migraine. We performed a PubMed search up to June 2018 targeting all peer-reviewed articles evaluating the changes in threshold, sensory phobia, or sensitivity in patients with migraine. Migraineurs, in general, exhibit lower sensory thresholds compared with healthy controls. These threshold changes seem to follow the different phases during a migraine cycle. In general, thresholds reach a nadir when the headache starts (the ictal phase), rise after the headache ends, and then gradually descend towards the next attack. The sensory modality of measurement—mechanical, thermal, or nociceptive—and the location of measurement—trigeminal vs somatic dermatome—also influence the sensory threshold. Functional imaging studies provide evidence that the hypothalamo-thalamo-brainstem network may be the driving force behind the periodic threshold changes. In summary, there is evidence in the literature that migraine could be understood as a periodic sensory dysregulation originating from the brain. Nevertheless, the interstudy discrepancy is still high due to different study designs and a lack of focus on distinct migraine phases. Further well-designed and harmonized studies with an emphasis on the cyclic changes still need to be conducted.

aDepartment of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

bBrain Research Center, National Yang-Ming University, Taipei, Taiwan

Corresponding author. Address: Department of Systems Neuroscience, University Medical Center Eppendorf, Hamburg, Martinistraße 52, 20246 Hamburg, Germany. Tel.: +49 40 741059189. E-mail address: a.may@uke.de (A. May).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received November 25, 2018

Received in revised form January 23, 2019

Accepted February 01, 2019

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1. Introduction

Although clinicians and scientists focus on the headache in migraine, a broad spectrum of symptoms other than headache occur which in part define this complex and multifaceted disease. These symptoms include hypersensitivity to a variety of different sensory stimuli, eg, light, sound, and smell, and are commonly present during37 and, to a lesser degree, also outside19 the headache attack. Consequently, focusing exclusively on the headache may prove to be oversimplifying this complex functional disease. From a physiological standpoint, there may be 3 processes that prompt sensory hypersensitivity in migraine: functional disturbance due to (1) habituation deficits; (2) cortical dysexcitability; and (3) aberrant functional connection of pain-processing networks.51 One could argue that cumulative nociceptive input, eg, in patients with high attack frequency, may also exert a modulatory effect on the neuronal networks that modulate sensitivity in migraine.73,85 Patients with migraine, compared with healthy subjects, exhibit a biological trait towards hypersensitivity; however, this irritability is further dependent on the phase during a migraine cycle. The following phases are defined in reference to their temporal relation with headache in a chronological order: (1) interictal—the interval between 2 headache attacks; (2) preictal—24 to 48 hours before the onset of headache; (3) ictal—the time when the patient experiences headache; and (4) postictal—24 to 48 hours after the completion of headache. The phasic changes of hypersensitivity are reflected in the habituation deficits and sensory phobia. In principle, migraineurs show a lack of habituation towards repeated sensory input during the interictal phase, but this habituation deficit “normalizes” 12 to 24 hours before the migraine attack,28,40,42,45 only to build up again in the postictal phase. Sensory phobias also oscillate in severity during the migraine cycle. Migraineurs with ictal photophobia already experience an increased sensitivity to light in the preictal and interictal phases.3,24,52,74 This suggests that sensory changes during a migraine cycle are a continuum across different phases with a different magnitude of sensitivity, peaking during the ictal phase. Since the sensory input does not change, the question arises whether perception changes are the consequence of peripheral or central alterations. No valid data exist that peripheral receptors change, although in principle, it is conceivable that receptor expression follows a periodicity. However, given the wealth of imaging data such irritability more likely represents an altered central processing of the incoming signals, ie, threshold shifts over time, the neuronal excitability within the trigeminal nerve and/or trigeminal pain-processing pathways varies spontaneously following a cycling pattern.74,75,83 The question still stands whether this cycling of neuronal excitability is due to facilitating or inhibiting neurons or brain regions, whether it is the consequence of an alteration in network connectivity, or indeed a (genetically determined) modulation in a certain receptor and/or channel.

A sensory threshold is by definition the weakest strength of a given stimulus that the subject can detect. A standardized stimulus precisely on the threshold level is therefore in 50% of applications detectable, and in 50% of applications nondetectable.81 Quantitative sensory test (QST) is a psychophysical method used to measure somatosensory function, and it has been validated with standardized protocols and reference values.66 A phasic threshold change in migraine was initially reported by Burstein et al.16 using QST: Patients exhibited a lower pain threshold during the ictal phase compared with the interictal phase. Despite the abundance of studies which examined QST differences in migraine vs controls, since then, it is surprising that few focused on the phasic changes—how thresholds behave over time in the migraine cycle. We hypothesize that periodic threshold changes are a highly sensitive indicator of migraine biology and may indeed represent the much sought-after “biomarker.” This hypothesis furthers leads to the theory that migraine may be understood as an oscillating threshold disease.

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2. Overview of different modalities of threshold changes in migraine

The concept of threshold changes in migraine is in the literature often implicit, but studies focused on “altered sensitivity,” “change of sensory phobia,” and others33 remain scarce. We performed a PubMed search up to June 2018 targeting all peer-reviewed articles evaluating the changes in threshold, sensory phobia, or sensitivity in patients with migraine. In the following paragraphs, the threshold changes and their symptoms, eg, phobia and allodynia, will be discussed.

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2.1. Somatosensory

Altered somatosensory perception is common among migraineurs in their ictal phase with the most prominent symptom being tenderness and irritability that extend beyond the cranial regions.39,49,87 Allodynia is reported in up to 80% of patients with migraine,5,12 either exclusively16 or more pronounced during the ictal phase,50 and as such a symptom of a decreased sensory threshold which can be verified using QST.16 Although allodynia is relatively specific during the ictal stage, interictal migraineurs also exhibit lower mechanical pain threshold95,98 and thermal pain threshold.27,70,76,77 In pediatric patients, a lower sensory threshold has also been reported, but modulating factors, such as sex and the presence of the subject's mother during the examination, seem to be particularly prominent in children.98

In general, thermal pain thresholds, especially heat pain thresholds, are lower in migraineurs than in healthy controls.8,27,68,76,77,90 Studies on mechanical threshold and cold pain threshold showed somewhat mixed results: Some reported decreased thresholds among migraineurs,70,95,98 while others showed no differences.8,90 Studies on pressure pain threshold are relatively abundant and mostly showed a reduced threshold according to a recent meta-analysis.56 Studies on the electrical pain threshold showed no difference between interictal migraineurs and healthy controls, but migraineurs exhibit higher suprathreshold pain ratings.8,32 Of note, most of these studies are “snapshots” in a single phase, ie, changes in sensitivity were not longitudinally investigated with consecutive measurements during the migraine cycle. This may explain the conflicting results. In such studies, patients were asked to keep a headache diary, and most participants reported an average of 1 to 4 migraine attacks per month. The examination date was retrospectively assigned into the respective migraine phases, leading to simple cohort studies. The data from different persons were then pooled for comparison, ignoring the high interpersonal variance in sensory thresholds, which may be one of the reasons explaining the discrepancy between studies.

A more remarkable factor in the discrepancy among studies is a surprisingly poorly differentiated definition of migraine phases: Until now, there is no international consensus for the term “interictal” phase, ie, a consensus when the preictal phase starts and the postictal phase ends. Any threshold 1 day before a migraine attack and 10 days before a migraine attack may differ greatly, but both may be regarded as “interictal phase.” Even the relatively simple definition of the ictal phase—the presence of headache—can be sometimes difficult. When a patient is effectively treated, the headache subsides, but the phase does not change immediately along with it. One large-scale study showed that the sensory threshold decreased continuously at least starting 7 days before the ictal phase.77 The conflicting results of somatosensory QST changes were recently reviewed,56 but a focus on the crucial phasic influence is still lacking.63

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2.2. Visual

Photophobia is one of the most prominent features during a migraine attack with a prevalence of 80% to 90% among migraineurs.65,67 Photophobia is relatively specific to migraine with a specificity of 74% and consequently has been used as 1 item in a validated 3-item screening tool for migraine—ID migraine.47 However, patients with migraine already exhibit in the interictal phase greater discomfort when exposed to light, compared with controls.24 The visual discomfort threshold to light luminance (Lux) has been shown to be significantly lower among interictal migraineurs vs healthy controls (95 Lux vs 200 Lux, P < 0.001).52 When the wavelength of the light was investigated more in detail, interictal migraineurs had lower discomfort thresholds for all wavelengths (blue, green, and red) with the lowest discomfort threshold of blue light. In the acute attack, however, migraineurs exhibited the best tolerance to green light (the highest threshold), but similar discomfort level to the light of the other spectrums.59 Interestingly, a recent animal model demonstrated that green light may exert antinociceptive effects,38 and in humans, green light compared with other colors is also least likely to exacerbate or to trigger a headache.58 In sum, the sensitivity to light is not only condition-dependent (migraineur > healthy control) but also phase-dependent (ictal phase > interictal phase).

Orientation discrimination is defined as the ability to differentiate minimal variation in orientation, and humans are usually capable to tell the acute difference of less than 1°. This task is based on inhibitory circuits in the visual cortex.7 Previous studies found that among migraineurs without aura and healthy controls, there were no discernible differences.96 However, migraineurs with aura exhibit a trend towards a deficit (higher threshold) in orientation discrimination,54 which seems to be associated with higher aura load.96 However, different migraine phases were not investigated.

Visual contrast gain control is the ability of neural adjustment to blurred images.93 Several studies consistently found that patients with migraine have a dysregulated visual contrast processing,10,11,78 suggesting a visual cortical dysfunction that extends also to the parietal and temporal cortices. Another study examining precortical functions of vision by examining the threshold of luminance of a moving target against an illuminated flickering background noise and reported that migraineurs with and without aura had a lower luminance detection, suggesting a precortical dysfunction.20 Interestingly, a recent study demonstrated that the threshold of luminance detection against background noise is condition-dependent (migraineur vs control), while the visual contrast processing is phase-dependent (ie, migraine phase), which weakens during the 48 hours preceding the headache attack and strengthens 24 hours after the attack.53

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2.3. Auditory

Phonophobia during attacks is part of the migraine definition and is very common among migraineurs ranging from 70% to 83%.43,62 Just as with photophobia, interictal phonophobia is also very common: up to 76% in an earlier epidemiological study.43 Quantitative measurement of sound-induced discomfort supported this earlier observation. The sound volume (median, 25th, and 75th percentile in dBA) required to induce discomfort was 111.2 (103.1-111.3) in healthy controls, 97.6 (89.8-107.1, P < 0.01) in interictal migraineurs, and 82.1 (76.0-87.2, P < 0.0001) during the ictal phase of a migraine attack.92 A later study that used standardized audiograms to examine sound aversion at different frequencies in migraine subjects described similar findings.3 Of note, this study eliminated those with migraine preventive medication because some migraine medications may exhibit a modulatory effect on sound sensitivity.3

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2.4. Olfactory

The prevalence of osmophobia ranges from 38.5% to up to 84% among patients with migraine, and the common scents include perfume, cigarette smoke, or certain kinds of food, in particular those with strong flavors.18,97 The high prevalence might be subject to recall bias because most studies used a retrospective questionnaire design without objective quantitative olfactory measures. Demarquay et al.25 used a chemical odor intolerance index to 5 different stimuli to examine olfactory sensitivity more objectively. In their migraine cohort, 35.2% reported osmophobia, and those with self-reported osmophobia indeed showed a higher intolerance score compared with healthy controls. Interestingly, even patients with migraine who reported no osmophobia during attacks still scored significantly higher than healthy controls.25 No study examined the olfactory threshold in migraineurs quantitatively, ie, using standardized concentrations of a specific compound to measure detection thresholds,21 and none correlated such findings to different migraine phases.

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2.5. Others

Migraine is accompanied with miscellaneous symptoms among which several manifest with oscillatory sensitivity changes across different phases in a migraine cycle, including emotional, cognitive, and autonomic symptoms.36 The fluctuating sensitivity of these symptoms reflects underlying detection threshold changes; however, in practice, certain symptoms are difficult to be measured or quantified due to a lack of proper tools. For example, most of the psychological batteries used to measure mood changes including anxiety or depression lack the sensitivity to detect day-to-day variance.64 Very few batteries are designed to measure day-to-day mood changes, but the application of them on patients with migraine has not been validated.23

In summary, most of the thresholds toward discomfort or pain including somatosensory, visual, or auditory thresholds showed consistent patterns: (1) Migraineurs have lower thresholds compared with healthy controls (conditional difference); (2) the threshold changes are related to and depend on the actual phase within the migraine cycle (phasic difference) (Fig. 1). (3) Some thresholds changes, ie, visual thresholds, seem specific to patients with migraine with aura. Conditional and phasic differences in threshold among migraineurs are summarized in Table 1.

Figure 1

Figure 1

Table 1

Table 1

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3. Altered thresholds in migraine: Where is the source?

It is intriguing that patients with phonophobia are more likely to also have photophobia and even allodynia.6 The cross-link between hypersensitivity of different sensory modalities suggests a common modulator behind different sensory threshold changes observed in patients with migraine.6

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3.1. Changes in the somatosensory threshold

A specific brainstem activation during the migraine attack has been known for more 20 years,94 and the role of the brainstem in migraine generation was further reinforced by recent neuroimaging findings: the response of trigeminal nuclei to nociceptive stimuli oscillates in different phases in a migraine cycle.83,84 Several nonheadache symptoms of migraine, ie, yawning, fatigue, and appetite changes, suggest a hypothalamus involvement in migraine attack,29,30 and a role of the hypothalamus was also supported by imaging findings.26 Since it has been shown that the response to noxious stimuli and the functional coupling among the hypothalamus, thalamus, and pons oscillates in a migraine cycle,75,83 a likely candidate for such oscillating threshold changes lies in the hypothalamo-thalamo-brainstem network.75,83 It needs to be pointed out that other brain structures may be also involved, and given the clinical picture of migraine, the most likely additional candidates are the limbic system and the nucleus accumbens. The sensitization of the trigeminal nucleus caudalis, which lies in the brainstem, is believed to mediate cephalic cutaneous allodynia during a migraine cycle.60 However, threshold changes extend beyond the trigeminal receptive field,15 and even stronger visceral pain was reported in migraineurs in comparison with health controls.57 One functional imaging study showed an increased activity of the posterior thalamus in ictal migraineurs with extracephalic allodynia,15 which suggests that allodynia in migraine may not only arise from sensitization of secondary neurons that reside in the trigeminal nucleus caudalis, but possibly also from tertiary neurons in the posterior thalamus. Nevertheless, the aforementioned imaging findings were from studies conducted during the ictal phase. One study examined how the brain changes during the interictal phase of migraine with thermal stimuli over the face and arm. They found a decreased response in the cuneiform nucleus in migraineurs compared with healthy controls, suggesting a possible dysfunctional descending inhibition of pain processing during interictal phases, hence leading to a higher neuronal excitability and therefore lower pain threshold.55

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3.2. Changes in visual thresholds

The neuronal networks controlling visual threshold vary greatly depending on the visual task performed. Dura sensitive neurons in the posterior thalamus are modulated by the projection from intrinsically photosensitive retinal ganglion cells, providing a neuroanatomical basis for photophobia.61 Another recent study revealed a visual-nociceptive integration at brainstem level at least in chronic migraineurs.73 Both suggest that the thalamo-brainstem complex might be the source of decreased visual threshold of discomfort, ie, photophobia. Of note, data from studies examining the deficits in visual contrast processing and the luminance threshold against background noise suggest a more generalized cortical dysfunction in migraineurs.10,11,20,53,78,93

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3.3. Changes in auditory thresholds

The brainstem may contribute to the threshold changes to sound, as brainstem auditory-evoked potentials revealed a trend toward potentiation over wave IV-V in migraine, in comparison with habituation that was seen in healthy controls.71 Patients with interictal migraine in comparison with healthy controls showed augmentation, instead of habituation, over the N1–P2 complex in intensity dependence of auditory-evoked potentials.2 The anatomical correspondent of N1–P2 complex originates from the Heschl's gyrus of both hemispheres, which may provide a possible explanation why the sensitivity to sound is independent to the side of the headache.46

In summary, a functional change of the hypothalamo-thalamo-brainstem networks remains the most plausible source behind most of the observed threshold changes in migraineurs. However, abnormal threshold modulations in patients with migraine are probably not restricted to these areas but involve the (perception specific) primary and association cortices.10,11,20,53,78,93 The “timeline” of symptoms during a migraine cycle may provide hints to the chronological involvement: While certain symptoms occurring during the premonitory phase, including appetite change, mood change, and sleep disturbance, are believed to originate from the hypothalamus,35,74 most common postdromal symptoms such as tiredness and difficulty in concentration are believed to reflect an altered processing at the cortical level.34 However, if the hypothalamus can modulate cortical processing or vision and olfaction,35,74 it could also influence the cortical processing of certain postdromal symptoms. Therefore, periodic sensory modulation may originate in the hypothalamo-thalamo-brainstem network but not restricted to the network. Given that nearly all sensory modalities are involved in one way or the other one could argue that the central nervous system, the “migraine brain” as such is different from a nonmigraine brain. It is probably more likely that some particular networks, “brain corridors” are involved, and the cortex only perceives what has been forwarded. Future work will need to disentangle which network is a driver of events and which ones may be just secondarily modulated.

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4. Threshold differences in subgroups of patients with migraine

4.1. Episodic and chronic migraine

Chronic migraine is rarely primarily chronic. In most cases, it evolves from an episodic form that gradually increases in frequency and attack duration.72,79 Multiple factors promoting migraine chronification have been identified, but the underlying pathophysiological mechanisms leading to an increase in attack frequency and duration and ultimately to migraine chronification are still unknown. Few studies evaluated the difference in sensory threshold between episodic and chronic migraine. Allodynia, a clinical symptom suggestive of a decreased pain threshold, seems more prevalent among chronic migraineurs than in episodic migraineurs (93% vs 81%, P = 0.03), although this study was conducted retrospectively using a questionnaire.9 Nevertheless, studies using objective measurement of allodynia, eg, brush allodynia or pressure allodynia, showed similar findings, ie, allodynia is more prevalent among chronic migraineurs.48 One study found patients with chronic migraine had lower thresholds for thermal pain during both interictal phase and ictal phase vs those with episode migraine,44 whereas another study found no difference in thermal or mechanical thresholds between episodic and chronic migraineurs; however, both groups had lower thresholds than healthy controls.76 It has to be taken into account that chronic migraine, by definition, presents with more than 15 days of headaches per month.37 Patients are therefore more likely to experience a headache on the day of the examination. The differences between chronic and episodic migraine described above may therefore result from a phasic change (ictal phase vs interictal phase), rather than a conditional change (episodic vs chronic migraine).

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4.2. Migraine with aura vs without aura

Most studies studying sensory thresholds in migraine enrolled patients with and without aura without differentiating between both forms. This was partially due to the fact that the statistical power was inadequate, as most of these studies only enrolled around 20 subjects in total.27,70,76 In one study, patients with migraine with aura seemed exceptionally vulnerable to the development of allodynia compared to those with migraine without aura (57% vs 33%, P = 0.03).4 As previously mentioned, orientation discrimination54,96 and discomfort score of photophobia24 are stronger among migraine with aura. These studies suggest that the extent of involvement in the brain, ie, brainstem or visual cortex, may be different between patients with and without aura, but the data are not sufficient to make a general statement.

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4.3. Menstrual cycle and its effect on sensory threshold

In both migraineurs and healthy subjects, sensory thresholds vary during a menstrual cycle. Pain thresholds are usually lower during menstruation86; while detecting thresholds are slightly increased in the early follicular phase and gradually decrease towards the ovulation.82,86 Periodic menstrual changes and migraine may modulate sensory thresholds synergistically. In one study, both healthy controls and migraineurs showed a reduced habituation and enhanced amplitude to laser-evoked potentials (LEPs) during the premenstrual phase. However, patients with migraine, compared with healthy controls, exhibited an even larger increase of amplitudes and therefore an even more reduced habituation.89 The reduced habituation during the premenstrual phase may further facilitate migraine attack during menstruation.89 This issue is little investigated, and future studies will need to control for menstrual cycle in female participants.

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5. Conflicting results and limitations in the literature

5.1. A focus on phasic changes is critical

The diagnosis of migraine relies on the diagnostic criteria that encompass attack-like behavior, head pain, and the presence of phonophobia and photophobia.37 Irritability to sensory input such as phonophobia and photophobia is simply a threshold alteration in detecting unpleasantness of incoming signals. All above named studies show unequivocally that patients with migraine exhibit sensory irritability—lower thresholds outside the attack,3,27,52,70,76,77 which extends beyond the trigeminal nociceptive area into all senses.14 It is therefore remarkable that we have to concede that we know little about phasic changes of thresholds in migraine. Phasic difference probably accounts for a great proportion of published interstudy differences. The evidence from the only available continuous longitudinal imaging study of migraine over 1 month,75 and another large scale physiological study using the time towards the next migraine attack as a continuous variable,77 both suggest that the perception of patients with migraine is strongly correlated to the migraine phase the patient currently is in.85 With a better understanding of dynamic phasic changes in migraine, another critical question may be eventually answered: Do patients with migraine exhibit a normal threshold that is comparable with that in healthy controls during a certain period in a migraine cycle, eg, early interictal phase? Or is there a continuous conditional difference between migraineurs and the healthy subjects?

Another confounding factor in the interpretation of thresholds is (its lack of) repeatability. The decision of a “normal threshold” for an individual is difficult, and sometimes, the within-individual day-to-day standard deviation (SD) is greater than between-individual SDs.68 To use a change of ≥1 between-individual SD to define allodynia16 is probably not sufficient. Preferably, a longitudinal study design and the use of coefficient of repeatability to measure day-to-day changes can reduce the within-individual variance.13

Another conceptual problem is the lack of internationally accepted definitions of the lengths of the preictal, postictal, and interictal phases. At the moment, it is completely unclear whether a preictal period should be 24 or 48 or 72 hours before the next attack and the same holds true for the postictal phase and consequently for the interictal phase. Until such a basic definition is not agreed on, studies are hardly comparable.

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5.2. Phasic threshold changes vs habituation deficits, is there a paradox?

Earlier visual-evoked potential (VEP) studies showed a habituation deficit in the interictal phase that subsequently normalized during the migraine attack.17,40,41,45,69,80 This seems contradictory to the threshold changes we reviewed: where such thresholds are already low interictally but decrease further during the ictal phase. At least 3 hypotheses account for such a difference: (1) the hypothesis of a decreased preactivation level in migraineurs stressing lower initial amplitudes (in the first block) during repetitive stimulation.22 A “ceiling effect” model could explain a possible relationship between decreased cortical excitability and a lack of habituation or potentiation of evoked responses.22 In this model, habituation in migraineurs depends on the preactivation level of cortical excitability that determines the range of activation before the “ceiling” is reached.1,85 Second, studies on LEP do not universally show a peri-ictal normalization as seen in VEP studies. Some reports showed that the LEP- habituation deficits persisted through the ictal phase.88,91 Third, habituation deficits mostly come from the studies on VEP and LEP, which are cortical responses to visual or noxious inputs.17,40,41,45,69,80,88 Generally, LEP reflects a mixture of both pain-specific activation and descending pain modulation.31 A better physiological representative of LEP is intensity of pain perception, instead of pain thresholds. Therefore, threshold and habituation changes reflect different modalities and do not contradict each other. The issue of habituation deficit has been reviewed elsewhere.51

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6. Conclusion

All sensory thresholds are dynamic during a migraine cycle, possibly driven by a genetically inherent periodic oscillation of the hypothalamo-thalamo-brainstem network. In general, sensory thresholds decrease during the interictal stage and reach a nadir during the headache pain attack, only to gradually recover afterwards.

In essence, this is what migraine represents—a cycling of neuronal excitability with the consequence of constantly changing sensory thresholds and thus perception. Of note, from a physiological perspective, the cycling is not specific for migraine. Strictly speaking, the cycling of neuronal excitability is the result of a cyclic component of something else (eg, ion channel expression). When we talk about a migraine cycle, we talk about a genetically determined clinical picture that reflects periodic changes in neuronal excitability which again reflects endogenous molecular oscillating rhythms. We have not yet understood who and where the real driver of such oscillating rhythms is to be found. Several questions remain to be answered: (1) Which modalities of threshold best represent the phasic changes in migraine; (2) what is the driving force behind the threshold changes; (3) are thresholds in migraineurs comparable with thresholds of healthy controls as a “normal” reference; (4) can the speed of change in the threshold be used as an indicator of disease severity; and (5) can it be modulated with treatment? A better understanding of thresholds and their oscillatory changes will provide a better perspective into migraine physiology.

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Conflict of interest statement

The authors have no conflict of interest to declare.

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Acknowledgments

This work was supported by the German Research Foundation, SFB936/A5. K.-P. Peng received a scientific fellowship from the international headache society and conference travel support from the Brain Research Center, National Yang-Ming University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The funding sources did not influence study conduction in any way.

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Supplemental video content

Video content associated with this article can be found at http://links.lww.com/PAIN/A762.

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Keywords:

Migraine; Threshold; Condition; Phase; Sensory

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