The present results show that prolonged migraine suffering is associated with changes in the diffusion properties of neuronal structures involved in trigeminal pain processing, the focus of this study. These findings represent changes that are not related to the migraine attack itself, because data were collected interictally.
Diffusion changes in the thalamocortical tract, corresponding to third order neurons, were present both types of migraineurs. The thalamocortical circuitry is based on mutual feedback loops that show marked plasticity [15
]. We interpret these changes as the possible consequence of frequent migraine attacks, with the presence of induced axonal adaptative response in the thalamocortical tract.
FA changes do not necessarily indicate lesions, and can be influenced by different variables such as myelination, axon diameter and axon density [9
]. In consequence, interpretation of the present data should also be considered from the functional perspective. Migraine patients present interictal functional abnormalities potentially related to trigeminal sensory system dysfunction, and clinicians have long been aware that migraine patients become abnormally sensitive outside attacks not just to light and sound, but also to cutaneous / mucosal stimuli [16
]. Migraine patients appear to not habituate to repetitive nociceptive stimuli [17
], and interictal thalamocortical somatosensory spike activity seems to be decreased in both migraine subtypes [18
]. Ultimately, this indicates that the thalamo-cortical tract is an important component of migraine pathophysiology, regardless of the migraine subtype. Pain modulates brain function and repetitive noxious stimulation induces long-term potentiation and hyperalgesia. The central sensitization observed in migraineurs is most probably related to an abnormal activity of the trigeminal sensory pathway.
Chronic or repetitive activation may modify grey and/or white matter structure [19
]. This has for example been shown in brains of individuals trained since childhood to play piano. The authors of this study [19
] found a positive correlation between the number of training hours and FA in the internal capsule, which can be interpreted as a result of an increase in the density
of myelinated axon. Paradoxically, intensive motor (piano) training results in lower FA values in the internal capsule of piano players compared to controls in two studies [19
]. This observation can be interpreted as an increase in axonal diameter
in the piano players. Training - or chronic use - may indeed have different results on white matter depending on whether it happens during brain maturation and myelination, or in the mature brain. Because repetitive, abnormally high frequency pain stimulation occurs in migraineurs, it is possible that low FA signals over the trigeminal sensory pathway do not reflect lesions in the brain, but rather an enlargement of axons as a response to over functioning.
One could argue that white matter changes could be related to cumulative lesions, from e.g. vascular origin. However, migraine-related lesions have a tendency to be located in posterior circulations areas [7
], and not to be related to any particular functional tract as is the case in our findings. The arrangement along a functional tract makes a vascular origin unlikely, and we conclude that the differences observed in migraineurs are most probably related to changes in function at molecular level.
As a critical pain neuromodulating structure, the periacqueductal grey matter has been implicated with the activation of the nervous system in migraine. The ventrolateral periacqueductal grey is part of a descending pain inhibiting system from the hypothalamus and frontal cortex projecting to the medullary and spinal dorsal horns. Periacqueductal gray activation inhibits contralateral trigeminovascular nociception in cats [22
]. Functional activation of the periacqueductal grey has been observed using PET during migraine attack [23
], and the periacqueductal grey of migraineurs contain more iron, a marker of cellular function, with levels increasing with the duration of the disease [24
]. We only found changes in the ventrolateral periacqueductal grey in migraineurs without aura, even if pain intensity and frequency was similar in both groups of migraineurs. These findings may indicate a possible dysfunction of the periacqueductal grey in migraineurs without aura, which could result in a lowering of the threshold for initiation of migraine attack through a lack of inhibition of the trigeminal sensory activation.
In conclusion, the data presented here show the presence of alterations in ascending (trigemino-cortical) and descending (periacqueductal gray) sensory pathways and structures in migraineurs, indicating an effect of migraine on the trigeminal sensory system at molecular level.
Further studies with larger amounts of patients are required for precise evaluation of possible pharmacologic influences; in addition, comparison with other headache disorders may indicate whether the findings reported in the present study are migraine-specific, or are the consequence of non-specific trigeminal sensory system chronic activation by corollary symptoms.