Figure 6. Magnetic source activation of high-gamma oscillations elicited by right finger movement.

Magnetic Source Imaging (MSI), the combination of magnetoencephalography (MEG) results and magnetic resonance imaging (MRI), shows the source activation elicited by right finger movement in both children with migraine and healthy controls. The red and yellow areas indicate regions of neuromagnetic activation (or synchronized neural firing). The neuromagnetic activation elicited by right finger movement is localized in the contralateral motor cortex in healthy controls (“Normal”). The neuromagnetic activation elicited by right finger movement is localized in the contralateral motor cortex as well as the premotor and supplementary motor areas in children with migraine (“Migraine”).

doi:10.1371/journal.pone.0050095.g006

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The activation value elicited by right finger movement in the children with migraine was stronger than that in controls (8102±2438 vs. 3509±2305, p<0.05). The results of ANOVA analyses showed that the strength of activation value during left finger movement was significantly affected by migraine (the group factor) (F = 21.35, p<0.001). Figure 5 and Figure 6 show the magnetic source image from two representative children with migraine and controls, respectively.

Discussion Top

The results of the present study have demonstrated that the abnormalities of motor function in children with migraine during headache attacks are noninvasively detectable using MEG and the abnormalities of motor cortical dysfunction can be characterized with the latency of MEFs evoked or elicited by finger movement [18]. Importantly, the delay of MEF components in children with migraine could be quantified in millisecond ranges [16]. Migraine is conventionally characterized by ictal episodes of moderate to severe episodic headache, which is described subjectively, leaving few clues for the study of migraine and for developing better therapeutic methods [19]–[21]. The confirmation of motor cortical dysfunction with quantitative neuromagnetic data suggests that a migraine headache attack is associated with cortical neurophysiological alteration. The neuromagnetic signatures of cortical neurophysiological alteration may provide a new objective biomarker for developing better therapeutic methods in the future.

One of the main findings in this study is that the positive correlation between responding latency and age in healthy children could not be found in children with migraine, showing the alteration of the developmental pattern in children with migraine compared with controls. The correlation efficient (or slope) differed between the two groups was also confirmed with the Fisher r-to-z transformation. Though aberrant brain activity in children with migraine during acute headache attacks has been found in the auditory, visual, and somatosensory systems [16], [22]–[25], studies of motor system activity in the developing brain during headache attacks in children have been very limited. One of the surprising findings in this study is that the delay in latency of MEFI and MEFII was not proportional to age in children with migraine. This raises the possibility of an abnormality in the developmental trajectory of motor cortical function. Since the brain maturation of motor function in healthy children is associated with a distinct pattern of developmental trajectory [5], [16], the results of the present study may indicate that the development of the motor function in children with migraine is neurophysiologically impaired or developmentally delayed. Of course, this needs to be confirmed by a similar study in these children in between headache attacks, which is ongoing in our institution at this moment. This hypothesis is supported by a previous EEG study that suggests that children with migraine lack an efficient coupling for integrating auditory and motor activation due to delayed frontal lobe maturation [22]. Braunitzer and colleagues have also found that the remarkable development of visual contour integration, which occurs between 6 and 14 years of age in the healthy subjects, is missing in migraineurs [23]. It seems that childhood migraine is not a benign or transient clinical semiology; instead, childhood migraine may affect the development of brain function and result in long-term problems.

It is unclear how migraine or headache attacks result in the delay of neuromagnetic response latency in the motor system in the developing brain. The aberrant latency observed in this study may be caused by the reductions in gray matter density in motor/premotor cortex [11], or/and the delayed white matter maturation [26]. The effect of migraine headache attacks on white matter integrity revealed by previous reports seems well in line with our observation because white matter integrity may directly affect the latency of neuromagnetic response [27], [28]. Since this is the first MEG study to address the developmental pattern of the motor system in pediatric migraineurs during acute migraine attacks, further investigation and verification are necessary. If this finding is true, it is clinically very important because better clinical treatment for childhood migraine can target at underlying neuropathology instead of simply relieving clinical headaches.

Our results have demonstrated that neuromagnetic high gamma oscillation activation in children with migraine can be noninvasively measured with MEG. Our data have shown that high gamma (65–150 Hz) oscillation activity is highly localized to the primary motor cortex in children with migraine and controls. The source locations indicated that these gamma oscillations were generated from the primary motor cortex that is consistent with previous reports [8], [29]. Therefore, MEG can be used to investigate the motor control of children with migraine. Muthukumaraswamy reported that this timing of gamma activity after movement onset suggests that these oscillations represent either afferent proprioceptive feedback or a relatively late stage of motor control [6]. The high gamma oscillations may reflect the activation of the cortical-subcortical networks during the onset of discrete movements or they may signal the direct modulation of the output of the subthalamic nucleus to the basal ganglia, thereby facilitating movement execution [29]. Our results show that high gamma oscillations are localized to the primary motor cortex in children with migraine, which may be important for functional mapping for children with migraine in the future.

Consistent with previous studies [16], [30], our data show the high gamma activation value in the patients was stronger than that in controls, which suggests that migraine is associated with increased brain response or hyper-activation. This result is also in line with the functional magnetic resonance imaging (fMRI) study, which has shown that migraineurs have greater activation in the primary motor cortex [31]. Although the underlying mechanisms of increased activation in the primary motor cortex remain unclear, one of the reasons may be the mutation of ion channels or transporters, which influence the glutamatergic synapses in the cerebral cortex in a way that results in release of excessive glutamate from neurons, reduced uptake of glutamate from the synaptic cleft into glia, and/or reduced buffering capacity to potassium ions [32]. Since it is the target of many new drugs that neural activation indicates cortical excitability [33], we consider those neuroimaging biomarkers will be important for developing better and more effective therapeutic strategy for children with migraine.

In conclusion, the abnormalities in the responding latency and source activation patterns suggest that there are neurophysiological changes in the motor cortices of children with migraine. The findings of this study may be helpful to further explore the underlying mechanisms of migraine and may facilitate the development of new therapeutic strategies in migraine treatment via alterations in cortical excitability. Recent reports have shown that normalization of cortical dysfunction may prevent and even cure migraine headache [30], [34]–[36]. Improved treatment and prophylaxis approaches based on better understanding of the mechanisms of migraine may effectively protect children with migraine from progressing into a chronic condition with significant disability later in life.

Date: 2016-03-03; view: 614