This study found widespread differences in the organization of WM between patients with CM and HCs. In addition, the diffusive metrics of episodic migraineurs, which did not differ significantly from those of HCs, also differed significantly from those of patients with CM.
Among the various techniques used to acquire MRI data, DTI is the most sensitive to microstructural changes by estimating the diffusivity of water molecules along the fiber bundles of WM in the three main orthogonal directions of diffusion. DTI metrics include FA, MD, AD, and RD. FA measures the fraction of the magnitude of the anisotropy; hence, it closely reflects the integrity of the membranes of the WM axons and directionality of the translational movement of the water molecules [24]. MD, which is comprised of radial and axial diffusivity and typically changes in opposition to FA, reflects the overall magnitude of water diffusion by indicating both cellular swelling and cellular density [24]. AD and RD diffusivity are considered to be in vivo surrogate markers of myelin and axonal damage, respectively. These metrics are closely associated with brain microstructure maturation processes as well as with higher levels of cognitive functions [25].
Several studies have shown plastic changes in WM microstructure during the interictal period in patients with migraine. Using a hypothesis-driven approach and a ROI analysis, most of this previous research was performed in patients with episodic forms of migraine; the authors found that – relative to HCs – patients with migraine showed altered DTI metrics in the thalami [10, 13], trigeminal somatosensory pathway [5], genu and the splenium of the CC [11], WM subjacent to area V3A and MT+, left lateral geniculate nucleus [4], and the optic radiations [6]. Whole-brain analyses have revealed contradictory results; indeed, both aberrant diffusive metrics [7, 12, 15, 26, 27] and no alterations [8, 9, 28] have been described in episodic migraineurs without aura when compared to controls. In agreement with the authors who did not detect microstructural abnormalities in patients with MO, we found no differences in the various metrics of diffusivity between patients with MO and HCs. These conflicting findings could be explained by the hypothesis that microstructural anomalies in patients with MO are of an insufficient size to be detected in a stringent statistical comparison with patients with CM, who feature prominent WM abnormalities. As highlighted by a few studies [9, 28], differences in acquisition and analysis parameters could also account for divergent findings.
Previous studies have failed to identify significant differences in DTI metrics between patients with CM and HCs. Part of the controversy can be ascribed to the inclusion of patients receiving preventives and/or overusing medication in a few studies, which could have altered the spontaneous course of the disease and thus biased the results [14, 15]. However, in one study, despite not having identified any significant anomalies in the CM population, the DTI metrics of patients with CM differed significantly from those with MO in several brain regions, including some whose microstructures were found to differ significantly between patients with CM and HCs in the present study [15]. Of such alterations, this study found the most prominent to be in the SCR and PCR, posterior limb of the IC, genu and splenium of the CC, and superior longitudinal fasciculus. These differences were especially evident when RD and MD diffusive metrics were considered. Furthermore, almost the same WM fiber tracts were detected to differ – albeit to a minor extent – between the patients with CM and those with MO, as revealed by a comparison of the corresponding FA and MD values.
The increases in the RD or MD DTI values in the CM group relative to the HC group may indicate axonal abnormalities and decreased cellular density in the WM of patients with CM. On the other hand, the decreased FA and increased MD DTI values of the CM group relative to the MO group might indicate a relatively more severe loss of directional organization and decreased cell density in patients with CM [29]. Moreover, since the swelling of glial cells (especially oligodendrocytes and fibrous astrocytes) could underly the FA changes [30], the morphological changes of glial cells in WM could also account for the altered FA values and, indirectly, MD values of patients with CM. Interestingly, bidirectional aberrant neuro-glial signal transduction has recently been proposed to be a key mechanism underlying chronic pain in general [31], and a genome-wide association study found an association between a gene expressed in glial cells and migraine [32].
Overall, most of the tracts found to exhibit abnormal WM diffusive metrics in the present study form parts of the widespread WM bundle fiber system of the brain that conveys information about somatosensory, cognitive, and/or emotional components of orofacial pain discrimination [33]. Other tracts, like the superior LF, seem to be involved in endogenous pain modulatory mechanisms and multisensory integration [34]. CM is associated with the inability to inhibit cognitive interference [35, 36], low cognitive reserve, and multisensory attention focusing, as well as cognitive deficits in multiple tasks – regardless of the use of medication or the presence of comorbidities – including verbal fluency, spatial dysfunction, and memory retrieval [37]. Thus, patients with CM may be less able to adopt appropriate coping strategies when confronted with daily or almost daily presentation of pain that limits the main activities of daily living. Nonetheless, the abnormalities in the microstructure of WM fiber bundles in patients with CM provide neuroanatomical evidence to support the hypothesis that dysfunctional central pain modulatory circuits contribute to migraine chronification.
Of note, the presently observed neuroradiological findings are similar to those found in relation to other types of cephalic and extra-cephalic chronic pain, such as trigeminal neuralgia [38], fibromyalgia [39], chronic musculoskeletal pain [40], and irritable bowel syndrome [41]. This consistency further supports the hypothesis that WM fiber bundles mediate pain perception and control, and that chronic pain of any type may account for the widespread disruption of WM integrity in the brain.
The WM fiber bundles found to be microstructurally peculiar in the CM group of the present study interconnect numerous and widespread cortical areas, many of those in previous functional resting-state MRI studies in patients with CM, have shown an altered connectivity at rest, including cortical areas belonging to the default, salient, and executive control networks, and their connectivity with the descending pain control system [42–45]. Indeed, in a previous study using the same cohort of patients, we found distinct abnormal connectivity patterns between frontal executive, dorsal attentional, and prefrontal-parietal default networks in patients with CM, as well as a correlation between such structural aberrations and headache severity [46, 47]. The headache severity was also related to the DTI metrics in the present study; the subjective perception of headache intensity was negatively correlated with FA and positively correlated with MD in the overlapping WM tracts of the right PCR in patients with CM and MO, respectively. Since the PCR forms part of the central pain modulatory circuit, and because a similar correlation was previously found in other chronic pain disorders [38, 41], it is possible that an abnormal microstructural integrity of the PCR compromises the perception of pain severity. However, since this was not a longitudinal study, we cannot exclude the possibility that, conversely, the intensity of the pain itself caused the microstructural integrity anomalies. Future studies using the same TBSS method are necessary to follow patients after preventive treatment, to investigate whether abnormal neuroradiological findings can return to normal in CM.
This study was subject to several limitations. First, we collected MRI data in only 30 diffusivity directions. This may have resulted in an underestimation of the degree of WM anomalies in our patients, especially those with MO. Second, the small sample size of the study may have biased our results; however, this limitation was not easy to overcome considering the difficulty of recruiting patients with pure CM and without preventive treatment or a history of drug abuse. Third, due to the lack of longitudinal data, it remains unclear whether the presently observed aberrant WM fiber bundle profiles in patients with CM is the consequence of migraine chronification or an abnormal brain maturation process manifesting early in life – as was shown in previous studies of pediatric migraine patients [48]. Fourth, we did not perform a cognitive assessment of these patients, which would have allowed us to better infer a causal relationship with the microstructural results. Finally, since psychiatric comorbidity and in particular chronic anxiety and depression, even if low-grade and untreated, could affect brain structure, further studies are needed to determine whether this type of comorbidity may have contributed to the microstructural abnormalities detected here.