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
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.
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.
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
The authors have no conflict of interest to declare.
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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