Our current findings show interictal thickening of the cortical mantle in the SSC of patients with migraine when compared with ageand sex-matched controls. Previous studies with chronic pain disorders, including migraine19
and back pain,20
have described abnormal variations in the frontal and temporal cortices using voxel-based morphometry, but not in the SSC. In one of their studies, Apkarian et al.20
measured cortical volume in chronic back pain patients and noticed thinning of the dorsolateral prefrontal cortex. However, chronic back pain is a disorder that initiates much later in life than migraine, which may influence the response of neuronal systems (adapta-tion/breakdown) to overstimulation caused by chronic pain. In addition, chronic back pain has relatively spread somatotopic distribution (pain occurs in multiple dermatomes) compared with migraine (trigeminal nerve), a fact that may explain their lack of reported changes in the SSC. The technique we applied is extremely reliable and sensitive to measure cortical thickness differences21
even in submillimeters with improved spatial localization, and uses of more stable structural parameters.22
Functional and structural plasticity in the so-matosensory cortex have been noticed in rats23
after altered sensory experience. In humans, a comparable thickening of the SSC at the border between the postcentral gyrus and sulcus has recently been reported in chronic stroke patients when compared with HCs.24
The area of thickening spatially coincided with blood oxygen level– dependent activation after tactile stimulation of the hemiparetic hand of those patients, which indicates coupled structural and functional cortical changes in the SSC. This observation is in line with colocalized functional and structural changes reported in the visual cortex of patients with migraine.9
The maximum degree of thickening observed in the SSC of stroke patients reached 13%, which is also similar to the degree of gray matter changes in the motor cortex,25,26
whereas in our migraine cohort the average group thickening magnitude in the SSC reached 21% (MWA vs HCs: right side), and in the control ROI thickening was not statistically significant. This higher degree of structural changes in the SSC of patients with migraine can be explained by the long-term overstimulation of sensory fields in the cortex induced by the frequent headache attacks, with most of our patients experiencing migraine since childhood (age at onset for all patients: 14.6 ± 5.9 years). This is consistent with increases in the sensorimotor cortex thickness or volume after extensive learning and training.12,13
We observed thickening of the lower segment of the posterior flank SSC, where the face and the head are somatotopically represented in both migraine groups.27
The area of cortical thickening was larger in the MWoA. Although each area of the SSC carries a parallel somatotopic map, with the craniofacial region represented caudally, its function differs in the anteroposterior extension.28
For example, in the central sulcus there are primarily cutaneous responses in minor trigeminal receptor fields. These receptor fields increase in size and complexity toward more posterior regions of the SSC, responding simultaneously to peripheral cutaneous and deep receptors, as well as integrating high-order corticocortical inputs.28
This suggests the cortical integration in the SSC of neuronal inputs from other cortical regions during the trigeminal noxious experience from the headache attacks in both migraine subgroups.
However, the structural changes in the SSC of both subgroups described here seem to be mostly related to the trigeminal somatosensory system. Thickening of the SSC was accompanied in the same migraine cohort by reduced fractional anisotropy (FA) in the subcortical trigeminal somatosensory pathway leading to the SSC.1
The tracts affected were the trigeminothalamic tract in the MWA group (second-order neurons) and the thalamocortical tract in both migraine subgroups (third-order neurons), MWA and MWoA. FA is a DTI parameter that reflects the diffusional property of molecules in the neuronal structures29
and may indicate for instance changes in the axonal diameter or integrity.30–32
These concomitant cortical and subcortical abnormalities may represent either an innate trigeminal hyperexcitability in migraineurs, or the result of sustained stimulation of the trigeminal somatosensory system provoked by migraine attacks.
It remains unexplained why the thickening in the MWoA group extended to anterosuperior regions in the SSC compared with MWA, which would have theoretically some implications to sensory receptors from other somatotopic regions of the body. The same MWoA cohort presented lower FA values in the ventrolateral periaqueductal gray compared with the MWA and control groups.1
The latter finding suggested a possible dysfunction of the descending modulatory system in our MWoAcohort, which could result in a lowering of the threshold for headache attacks and general pain through a lack of inhibition of the sensory inputs from the trigeminal and nontrigeminal areas of the body. Hence, the cortical changes in the sensory cortex of this MWoA group would not be restricted to the craniofacial somatotopic regions. Further studies should be conducted with a higher number of patient to determine whether these gray and white matter changes are specific to the patient cohort studied or the pathophysiologic trait of migraine in general.
Regarding the laterality of the migraine attacks, some of our MWA patients described that their headache attacks were ipsilateral to the visual aura. Although migraine is usually described as unilateral, its occurrence may alternate between sides, which is true for both headache and aura attacks. Although patients were almost always certain about the predominant laterality of the headache initiation (in percentage), the retrospective description of the aura side (visual field affected) regarding the headache potentially lead to some confusion for the patients. In the beacon prospective study by Russell et al.,33
it was stated that the unilateral aura/headache symptoms with contralateral occurrence was 90%, but 10% of the patients had headaches ipsilateral to the aura. Perhaps the ipsilateral occurrence was in fact a clinical characteristic in some of our MWA patients. Another factor is that headache attacks may initiate on both sides after the aura event (bilateral); in this case, both answers (ipsilateral and contralateral) are right. Nonetheless, is possible that the side predominance of the headache attacks may influence the cortical thickness pattern in both migraine subgroups. In the MWoA group, where there is an equal distribution of headache attacks regarding predominant side initiation (4 left/4 right/4 bilateral), the area of thickening in the SSC is relatively equal in both hemispheres. In the migraine with aura group though, where there is bias distribution of migraine attack on the left side (4 left/2 right/6 bilateral), the area of thickening in the SSC is larger in the contralateral right hemisphere. However, additional studies with more patients should be conducted in the future using fMRI and prospective data to investigate in details the laterality issue.
In conclusion, the current findings of gray matter thickening of the SSC in addition to the previous discovery of white matter diffusional changes in the trigeminal somatosensory pathway of the same migraine cohort indicate that somatosensory mechanisms are important components in the migraine pathophysiology. These cortical and subcortical changes may be either the result or cause of repetitive migraine attacks, which may also affect other systems.1,9
This may explain the high comorbidity of migraine with other pain disorders, including back pain,34
besides sensory disturbances such as allodynia.37