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Background.— Migraine is generally considered a functional brain disorder lacking structural abnormalities. Recent magnetic resonance imaging (MRI) studies, however, suggested that migraine may be associated with subtle brain lesions.
Objective.— We evaluated the presence of global or focal gray or white matter alterations in migraine patients using voxel-based morphometry (VBM), a fully automated method of analyzing changes in brain structure. VBM data also were used to evaluate possible differences between episodic and chronic migraine.
Methods.— Twenty-seven migraine right-handed patients and 27 healthy controls were selected for the study. Sixteen patients fulfilled the International Headache Society criteria for episodic migraine and 11 for chronic migraine. MRI scans were analyzed with MATLAB 6.5 and SPM2 software, using VBM method.
Results.— In comparison with controls, migraineurs presented a significant focal gray matter reduction in the Right Superior Temporal Gyrus, Right Inferior Frontal Gyrus, and Left Precentral Gyrus. Chronic migraine patients, compared to episodic, showed a focal gray matter decrease in the bilateral Anterior Cingulate Cortex, Left Amygdala, Left Parietal Operculum, Left Middle and Inferior Frontal Gyrus, Right Inferior Frontal Gyrus, and bilateral Insula. Considering all the migraine patients, a significant correlation between gray matter reduction in anterior cingulate cortex and frequency of migraine attacks was found.
Conclusions.— Our study shows that migraine is associated with a significant gray matter reduction in several of the cortical areas involved in pain circuitry. In addition, we found a significant correlation between frequency of migraine attacks and signal alteration in the Anterior Cingulate Cortex. Our data provide new insight into migraine pathophysiology and support the concept that migraine may be a progressive disorder.
Migraine is a primary headache disorder characterized by recurrent attacks of throbbing pain associated with neurological, gastrointestinal, and autonomic symptoms.1 In the U.S.A., migraine affects approximately 18% of females and 6% of males.2 According to the World Health Organization (WHO), migraine ranks among the world's most disabling medical illnesses.3 Migraine is generally considered an episodic brain disorder. However, approximately 20% of migraine patients develop chronic migraine, a condition characterized by the presence of frequent headache attacks.4 Patients with chronic migraine demonstrate remarkable impairment of their daily activities and are severely burdened by their headache syndrome.5
According to the Second Edition of International Classification of Headache Disorders (ICHDII)6 structural brain lesions are absent in primary headaches. Contrarywise, recent studies with voxel-based morphometry (VBM), a fully automated method of analyzing changes in brain structure, demonstrated selective brain alterations in both cluster headache and chronic tension-type headache. Cluster headache is characterized by a bilateral increase of gray matter in posterolateral hypothalamus7 while, in patients with chronic tension-type headache, a gray matter decrease was found in orbifrontal cortex, insula, and anterior cingulate cortex.8 In patients with migraine a previous VBM study did not detect any change in the structure of the brain.9 However, several functional imaging studies have shown that, during migraine attacks, there is an abnormal metabolism in several cortical and subcortical brain regions, suggesting a dysfunctional pain system.10,11
The purpose of this study was to investigate the presence of structural brain abnormalities in patients with migraine using the optimized VBM method, a highly sensitive technique to detect focal gray and white matter abnormalities in the brain.12,13 We compared the VBM data of a group of right-handed migraine patients, recruited from an university-based headache center, with those of healthy controls and we searched for global and local differences in gray and white matter. We further analyzed VBM data of the patients in order to look for structural brain differences in migraine subgroups and we evaluated correlations with the clinical characteristics of the disease.
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Our study shows that in patients with migraine there is a significant gray matter decrease in several of the brain areas that belong to the central pain network. In comparison with controls, our right-handed migraineurs presented a significant gray matter reduction in the Right Superior Temporal Gyrus with extension to the Parietal Operculum, Right Inferior Frontal Gyrus, and Left Precentral Gyrus. When we divided our patients into episodic and chronic, we found that chronic migraineurs present a gray matter decrease mainly in the bilateralACC. Other clusters were found in Left Amygdala, Left Parietal Operculum, Left Middle and Inferior Frontal Gyrus, Right Inferior Frontal Gyrus, and bilateral Insula. Finally, examining the clinical features of our patients, we found a significant correlation between frequency of migraine attacks and signal alteration in the Anterior Cingulate Cortex.
Our data are not in accord with a previous study9 showing no structural changes in the brain of patients with migraine. There are some methodological differences that may explain the discrepancies between the 2 studies. The previous study examined only patients with episodic migraine and the VBM data have been analyzed using SPM99, an older version of the statistical parametric mapping software.
Recently, Rocca et al studied a group of migraine patients showing T2-weighted MRI white matter abnormalities. Using diffusion tensor magnetic resonance imaging, a new technique with the potential to disclose subtle abnormalities in the brain, a significant reduction of gray matter density was found.20 In a following study, in agreement with our findings, optimized VBM analysis localized in the frontal and temporal lobes the areas of reduced gray matter density.21 Finally, it is of interest to note that Welch et al, using high-resolution magnetic resonance imaging, demonstrated a significant correlation between the frequency of migraine attacks and iron deposition in the periaqueductal gray matter (PAG), one of the most important centers of the descending antinociceptive neuronal network.22 These data show some similarities with the results of our study and suggest that repeated migraine attacks may induce structural abnormalities in the pain modulating structures within the central nervous system.
Modern neuroimaging techniques have produced a significant advance in our knowledge about the neural circuitry involved in nociceptive processing within the brain. There are several cortical and subcortical brain regions that are differently activated by pain in different experimental conditions, including frontal and prefrontal cortices, operculo-insular cortex, primary and secondary somatosensory cortices, anterior cingulate cortex, thalamus, insula, basal ganglia, cerebellum, amygdala, hippocampus, and regions within the parietal and temporal cortices.23,24 In our study we found a gray matter reduction in several of the centers of this cerebral pain network. Our data may contribute to explain the abnormal processing of pain as well as the reduced pain threshold found in several neurophysiological studies of patients with migraine.25-28
The anterior cingulate cortex regulates a wide variety of autonomic functions and is vital to cognitive functions, such as reward anticipation, decisionmaking, empathy, and emotion.29 Recent neuroimaging studies suggested that ACC plays a key role in the affective and attentive concomitants of pain sensations.30 The selective alteration of the cerebral structures that modulate the affective components of pain found in migraine suggests a possible neurobiological mechanism explaining the link between chronic migraine and psychiatric disturbances.31–33 In addition, our data support the results of previous studies suggesting that migraine may be considered a progressive brain disorder34,35 and suggest a radical reappraisal of the guidelines for the prophylactic antimigraine therapy, in order to avoid the progression of the disease.
The possible mechanisms underlying the gray matter reduction in migraine are currently unknown. Voxel-based morphometry detects variations of gray matter concentration per voxel as well as changes of the classification of individual voxels, eg, from white to gray matter.12,13 The observed gray matter decrease may reflect tissue shrinkage (changes in extracellular space and microvascular volume) as well as more complex processes as neurodegeneration. So, there are several possible explanations for the abnormalities observed in our patients. Gray matter changes might result from repeated ischemia caused by the cerebral blood flow abnormalities observed both during migraine attacks and in the interictal phase.36,37 On the contrary, the gray matter reduction may be a consequence of migraine specific neurotoxic mechanisms. It has been hypothesized that migraine is associated with a state of neuronal hyperexcitability, involving overactivity of the excitatory amino acids glutamate and aspartate.38 A low brain magnesium and consequent reduced gating of glutamatergic receptors could be another possible link between migraine and the mechanisms of glutamate toxicity.39 Additional longitudinal functional and structural MRI studies are needed to elucidate the mechanisms underlying gray matter abnormalities in migraine and to evaluate the possible specific physiopathologic role of structural changes found in gray matter.
In conclusion, our work indicates that the brain of migraine patients is characterized by focal structural abnormalities. VBM analysis showed that migraineurs present a significant gray matter reduction of several brain areas belonging to the pain transmitting network. In addition, we found a significant relationship between signal reduction in the anterior cingulated cortex and the frequency of headache attacks, suggesting an important role for this area in the process of migraine transformation from an episodic to a chronic brain disorder. Our data provide new insight into our understanding of migraine pathophysiology and support the concept that migraine is not just an episodic disorder but may be a chronic progressive disorder. Ongoing research and new emerging therapeutic strategies should consider this change in the conceptual model of the disease.