Abnormal cortical activation in females with acute migraine: a magnetoencephalography study.

Clinical Neurophysiology xxx (2014) xxx–xxx

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Abnormal cortical activation in females with acute migraine: A magnetoencephalography study Huai T. Ge a, Hong X. Liu a, Jing Xiang b, Ai L. Miao a, Lu Tang a, Qing S. Guan a, Ting Wu a, Qi Q. Chen c, Lu Yang c, Xiao S. Wang a,⇑ a b c

The Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China The MEG Center, Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA The MEG Center, Nanjing Brain Hospital, Nanjing, Jiangsu, PR China

a r t i c l e

i n f o

Article history: Accepted 31 March 2014 Available online xxxx Keywords: Migraine Magnetoencephalography (MEG) Magnetic source imaging (MSI)

h i g h l i g h t s It is well known that cerebral cortex plays a key role in migraine attacks and movement makes

migraine headaches worse; however, its neural mechanism is poorly understood. Finger movements produced cortical hyperexcitability in females with migraine during migraine

attack in a frequency range of 5–1000 Hz. Neuromagnetic signal may help to identify neurophysiological biomarkers for studying mechanisms

of migraine using MEG and may facilitate to develop new therapeutic strategies for migraine.

a b s t r a c t Objective: The objective of this study was to investigate functional abnormalities of the brain in females with migraine using magnetoencephalography (MEG) and a finger-tapping task. Methods: Twenty-nine female patients with migraine (aged 16–40 years) and age- and gender-matched healthy controls were studied with an MEG system at a sampling rate of 6000 Hz. MEG recordings were performed during an attack in migraineurs with and without aura. Neuromagnetic brain activation was elicited by a finger-tapping task. The latency and amplitude of neuromagnetic responses were analyzed with averaged waveforms in the frequency range of 5–100 Hz. The Morlet wavelet and beamformers were used to analyze the spectral and spatial signatures of MEG data from subjects in two frequency ranges of 5–100 and 100–1000 Hz. Results: The latency of motor-evoked magnetic fields evoked by finger movement was significantly prolonged in migraineurs as compared with controls. Neuromagnetic spectral power in the motor cortex in migraineurs was significantly elevated. There were significantly higher odds of activation in 5–30, 100–300 and 500–700 Hz frequency ranges in the ipsilateral primary motor cortices and the supplementary motor area in migraineurs as compared with controls. Conclusions: Neuromagnetic signal abnormalities in this study suggest cortical hyperexcitability in females with migraine during migraine attack, which could be measured and analyzed with MEG signal in a frequency range of 5–1000 Hz. Significance: These findings may help to identify neurophysiological biomarkers for studying mechanisms of migraine, and may facilitate to develop new therapeutic strategies for migraine by alterations in cortical excitability. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author. Address: Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Guang Zhou Road 264, Nanjing, Jiangsu 210029, PR China. Tel.: +86 025 82296208; fax: +86 025 83719457. E-mail address: [email protected] (X.S. Wang).

Migraine is a common disabling headache disorder characterized by ictal episodes of moderate-to-severe focal pulsating

http://dx.doi.org/10.1016/j.clinph.2014.03.033 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Ge HT et al. Abnormal cortical activation in females with acute migraine: A magnetoencephalography study. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.033

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H.T. Ge et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

headache (Coppola and Schoenen, 2012). Migraine sufferers are typically hypersensitive to visual (photophobia), auditory (phonophobia), and sensory (cutaneous allodynia) stimuli during migraine attack (Gelfand et al., 2010). Migraine frequently begins in childhood and the prevalence increases in adolescence and early adult life. The prevalence of migraine is the same in boys and girls before adolescence; it increases predominantly in females compared with males after puberty (Hershey, 2010). According to the World Health Organization, migraine has become one of the 20 most disabling diseases (Leonardi et al., 2005). The occurrence of frequent headaches can have a significant impact on the human quality of life (Gladstein and Rothner, 2010). It is therefore a public health problem having a great impact on both the individuals and the society. The neurobiological mechanism underlying migraine attacks remains unclear. There are evidences that the cerebral cortex plays a key role in migraine attacks (Hershey, 2005, 2010; Hershey et al., 2007; Pietrini et al., 1987). Bowyer and colleagues have found that patients with migraine have cortical hyperexcitability (Bowyer et al., 2005). Neurophysiological reports have shown that migraine is associated with abnormal excitability in visual and somatosensory cortices (Bowyer et al., 2001; Gunaydin et al., 2006; Lang et al., 2004). Recent magnetoencephalography (MEG) studies revealed that children with migraine, during their headache attacks, have significantly prolonged latencies of neuromagnetic activation in a low-frequency range, with increased spectral power in high-frequency ranges (Xiang et al., 2013; Wang et al., 2010). The spread of abnormal brain activation triggered by movements seems to play an important role in the cascade of pediatric migraine attacks (Xiang et al., 2013). As age is an important factor in headache severity, duration, frequency, and subsequent secondary disability (Bohotin et al., 2002), it remains unknown if adult patients with migraine are also associated with motor cortical dysfunction during migraine attacks. The involvement of motor cortex in migraine has drawn attention recently (Esposito et al., 2012; Conforto et al., 2012; Wang et al., 2010). It is well known that movement makes migraine headaches worse, and one subset group of migraine patients shows hemiplegia (Scherer et al., 1997); however, its neural mechanism is poorly understood. Reports on nonfamilial migraine with unilateral motor symptoms (MUMSs) showed that a syndrome of severe migraine with accompanying give-way weakness is common in tertiary care headache centers (Young et al., 2007). An increasing list of transcranial magnetic stimulation (TMS) reports indicates that motor cortical dysfunction may play an important role in the pathogenesis of attacks of migraine (Aurora et al., 1999; Conforto et al., 2012; Conte et al., 2010; Fumal et al., 2003; Khedr et al., 2006; Maertens et al., 1992). From a therapeutic point of view, high-frequency repetitive TMS (rTMS) of the motor cortex can normalize aberrant intracortical inhibition during migraine (Brighina et al., 2010). Neurophysiologically, rTMS of the motor cortex can also modulate pain-related evoked responses in migraine (de Tommaso et al., 2010). Of note, a clearer understanding of motor cortical activation in patients with migraine is scientifically and clinically important. The objective of the present study was to investigate motor cortical dysfunction in female adults with migraine using MEG and a finger-tapping task. We focused on females because the majority of patients with migraine are females and the ratio of migraine in female and male is approximately 3:1 (Hershey, 2012; Buse et al., 2012). A finger-tapping task was used because the task could activate the motor cortex without causing significant head movement. Our central hypothesis is that neuromagnetic activation in the motor cortex in females with migraine is significantly altered as compared with controls. To our knowledge, this is the first MEG study focusing on abnormalities of brain activation in the

5–1000-Hz frequency range in female adults with migraine using waveforms, spectrograms, and magnetic source imaging (MSI). Findings of this study may contribute to a better understanding of the mechanisms of migraine, and to the development of new therapeutic strategies in the future. 2. Methods 2.1. Subjects Twenty-nine female patients with acute migraine (mean age: 30.59 years; standard deviation: 5.75 years, range: 16–40 years) were recruited from Nanjing Brain Hospital (see Table 1). Six of them had aura, while the remaining did not. Twenty-nine agematched healthy female controls (mean age 30.59 years; standard deviation 5.75 years, range: 16–40 years) were recruited. All subjects >18 years of age signed a consent form. For subjects .05, see Table 3).

Table 2 The main dependent variables analyzed in the MEG spectrograms for ictal migraine subjects and controls. Analysis frequency

Measure variables

Movement finger

Migraines

Controls

p Value

5–100 Hz

Latency 1 (ms)

Left Right Left Right Left Right Left Right Left

40.72 ± 7.19 42.96 ± 9.09 94.89 ± 10.25 101.51 ± 9.53 663.13 ± 147.06 736.82 ± 161.69 484.44 ± 126.20 522.62 ± 97.88 Right MA(29/29) Left MA(10/29) Right SMA(3/29) Left MA(29/29) Right MA(13/29) Left SMA(2/29) 3.1 ± .4 3.2 ± .65

27.61 ± 4.32 27.53 ± 3.51 78.79 ± 5.58 80.71 ± 3.88 706.71 ± 150.86 703.76 ± 100.28 525.08 ± 115.41 493.47 ± 72.55 Right MA(29/29) Left MA(2/29) Right SMA(1/29) Left MA(29/29) Right MA(3/29) Left SMA(2/29) 2.8 ± .35 2.9 ± .4

0.5 >0.5 >0.5 .42 .89

Right MA(6/6) Left MA(1/6) Right SMA(2/6) Left MA(6/6) Right MA(1/6) Left SMA(2/6) 2.63 ± .35 2.89 ± .11

Right MA(23/23) Left MA(3/23) Right SMA(8/23) Left MA(23/23) Right MA(3/23) Left SMA(8/23) 2.68 ± .40 2.94 ± .54

>0.5 >0.5 >0.5 >0.5 >0.5 >0.5 .210 .144

Abbreviations: MA, primary motor area; SMA, supplementary motor area.

Fig. 2. Polarity spectrograms (first and third row) and contour maps (second and fourth row) of neuromagnetic signals in 5–100 Hz frequency band recorded from a migraine subject and a control during finger movement. There are at least two components indicated by numerals 1, 2, and/or 3 in the polarity spectrograms, and the components are in a frequency band of 5–30 Hz. The contour maps show the activation of cortex of migraine and control. Of note, the migraine subject has activation outside of the primary motor cortex. There are no significant differences of spectral signatures between the subgroups migraine with aura (MwA) and migraine without aura (MwoA).

3.3. Time–frequency in two frequencies ranges The polarity spectrograms revealed that there were at least two oscillatory components in all patients and controls in the

frequency range of 5–100 Hz, especially in the frequency band of 5–30 Hz (e.g., see Fig. 2). Interestingly, there was no significant difference in averaged spectral power in the frequency range of 5–100 Hz between migraine patients and controls. The source


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patterns were analyzed with spectral contour maps. The contour maps showed that the activation of neuromagnetic responses was localized in the contralateral hemispheres in both migraine subjects and controls, while the activation of neuromagnetic responses was localized in the ipsilateral hemispheres predominantly in migraine subjects. The polarity spectrograms showed that the source power activity in 100–1000 Hz frequency range was significantly increased in all migraine and control subjects after finger movement. Fig. 3 shows the time–frequency plot during finger movement. The glaring activation was found to be in 100–300 and 500–700 Hz frequency bands following the finger movement. Subjects with migraines showed stronger spectral power when compared with the controls in the 100–1000 Hz frequency range during finger movements (see Table 2). We also compared the spectral power between the migraineurs with aura and without aura during the left and right finger movements (see Table 3 and Figs. 2 and 3). There were no statistical differences between the two groups of patients in terms of spectral powers in the frequency bands of 5–100 and 100–1000 Hz. The contour maps revealed that the region of activation elicited by finger movement was beyond the primary motor area in migraine subjects, while it was limited to primary motor area in control. 3.4. Source analysis The MSI showed that the main activation of neuromagnetic responses in the frequency band of 5–30 Hz was localized to the contralateral primary motor area in all subjects with migraine

(29/29) and controls (29/29). Notably, migraine subjects had significantly higher odds of activation in the ipsilateral primary motor area (iMA) compared to control during finger movement (left finger: 10/29 vs. 2/29, p < .05; right finger: 13/29 vs. 3/29, p < .05; see Table 2 and Figs. 4 and 5). Strength of activation in the ipsilateral primary motor area (MA) between migraine subjects and controls was significantly different (p < .05, see Table 2). There were no significant differences between migraineurs with aura and migraineurs without aura (see Table 3 and Fig. 6). In the frequency band of 100–300 Hz, the MSI showed that the main activation of neuromagnetic responses during finger movement was located in the contralateral primary motor cortex in all migraine subjects (29/29) and controls (29/29). We found that migraine subjects had significantly higher odds of activation in the supplementary motor area (SMA) compared to control (left finger: 10/29 vs. 2/29, p < .05; right finger: 10/29 vs. 2/29, p < .05; see Table 2 and Figs. 4 and 5). There were significant differences in the strength of activation in the ipsilateral supplementary motor area (iSMA) between migraine subjects and controls (p < .05, see Table 2). There were no significant differences between migraineurs with aura and migraineurs without aura (see Table 3 and Fig. 6). The region of activation in frequency band 100–300 Hz was similar to that in 500–700 Hz band. Fig. 4 shows an example of MSI of a migraine subject and a control in 5–30 and 100–300 Hz frequency bands in 2D. Fig. 5 shows the probabilistic maps of the region of activation evoked by finger movement. The MSI revealed that the neuromagnetic activation in migraine was intensive and beyond the primary motor.

Fig. 3. Polarity spectrograms (first and third row) and contour maps (second and fourth) of neuromagnetic signals in 100–1000 Hz frequency band recorded from a migraine subject and a control during finger movement. There is increased spectral power in two frequency bands of 100–300 and 500–700 Hz in the polarity spectrograms. The contour maps showed the activation of cortex of migraine and control. The migraine subject shows increased activation. There are no significant differences between the subgroups migraine with aura (MwA) and migraine without aura (MwoA).



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Fig. 4. Magnetic source imaging (MSI) shows the source of activation of neuromagnetic response elicited by finger movement in 5–30 and 100–300 Hz frequency bands in a migraine subject (migraine) and a control (control). The red and yellow areas indicate regions of neuromagnetic activation (or synchronized neural firing). The color bar indicates the color coding of strength of activation. The neuromagnetic activation elicited by finger movement is localized in the contralateral motor area (MA) in healthy controls. The neuromagnetic activation elicited by finger movement is localized in the contralateral motor area (MA), the supplementary motor area, and the ipsilateral motor area in females with migraine (white arrows). The ‘‘L’’ indicates left, the ‘‘R’’ indicates right, the ‘‘A’’ indicates anterior, and the ‘‘P’’ indicates the posterior. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5. The number of migraine subjects and control in different neuromagnetic activation areas elicited by finger movement in 5–100 Hz (A) and 100–1000 Hz (B) frequency bands. (A) In the 5–100 Hz frequency band, migraine subjects have significantly higher odds of activation in the ipsilateral primary motor area (MA) compared to control during finger movement. (B) Migraine subjects have significantly higher odds of activation in the supplementary motor area (SMA) compared to control. Abbreviations: LFMLMA, left finger movements-left motor area; LFM-SMA, left ginger movement-supplementary motor area; REM-RMA, right finger movement-right motor area; RFM-SMA, right finger movement-supplementary motor area. ⁄p < .05.

4. Discussion The present study investigated neuromagnetic activation in female patients with migraine during headache attack periods using conventional measurements of waveforms, spectrograms, and newly developed source localization methods (Chen et al.,

2011; Wang et al., 2010; Bowyer et al., 2001). The waveform analysis was based on an averaging of multi-trial MEG data. Averaging keeps time- or phase-locked signals while minimizing timevariable signals (such as random noise). Spectral and source localizations based on wavelet and beamformer, on the other hand, were developed to analyze elicited brain activation which can be


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Fig. 6. Magnetic source imaging (MSI) shows the source of activation of neuromagnetic elicited by finger movement in 5–30 and 100–300 Hz frequency bands in a migraine with aura (MwA) and migraine without aura (MwoA) subgroups. The neuromagnetic activation elicited by finger movement is localized in the contralateral motor area (MA), the supplementary motor area, and the ipsilateral motor area (white arrows). There are no significant differences between migraine with aura and migraine without aura. The ‘‘L’’ indicates left, the ‘‘R’’ indicates right, the ‘‘A’’ indicates anterior, and the ‘‘P’’ indicates posterior.

non-time-locked brain activation. The present study has provided evidences that motor cortical dysfunction in female patients with migraine during a headache attack could be identified in MEG waveforms, spectrograms, and MSI. The neuromagnetic signatures of motor cortical dysfunction are potential new biomarkers for better understanding neural mechanisms of migraine as well as clinical management of patients with migraine in the future. There were no significant differences in MEG measurements between the subgroups of migraine subjects (with aura and without aura). This result might have been due to the absence of aura attack during the MEG recording in the subgroup of migraineurs with aura in the present study. Consequently, the effect of aura on neuromagnetic activation might have already subsided because of the absences of aura. The results of MEG waveforms and spectral data revealed that the latency of movement-elicited brain activation was significantly delayed in female subjects with migraine as compared with controls. This finding supports the notion that migraine is probably a primary neurological disorder instead of a vascular disorder (Charles, 2012). The cerebral mechanisms of the delay of movement-evoked brain responses remain unknown. Previous reports have demonstrated that white matter integrity may directly affect the latency of neuromagnetic response (Dockstader et al., 2012; Rocca et al., 2003). Since migraine is associated with white matter impairments (Rocca et al., 2003), the delay of movement-evoked brain responses might be resulted from white matter abnormalities. Another possible reason is the reduction in gray matter density in motor/premotor area in migraine patients (Kim et al., 2008), which may be related to the delay in latency of movement-evoked brain responses. The results of the present study also showed that motor cortical activation in female patients with migraine was significantly stronger when compared with that in the controls. This observation is

consistent with previous MEG studies (Wang et al., 2010; Bowyer et al., 2005). Increased brain activation has been considered to be a result of cortical hyperexcitability (Restuccia et al., 2012; Chen et al., 2012; Brigo et al., 2012). One of the possible explanations of cortical hyperexcitability is alterations of ion channels or transporters, which influence the glutamatergic synapses in the cerebral cortex (Moskowitz et al., 2004). Although the underlying mechanisms of increased cortical activation remain unclear, cortical excitability is the target of many new treatments (Bowyer et al., 2005). Bowyer and colleagues have shown that valproate can significantly affect cortical activation and MEG can noninvasively detect the changes before and after treatment (Bowyer et al., 2005). Of note, MEG assessment of cortical activation may play an important role in developing better and more effective therapeutic interventions for migraine in the future (Hershey et al., 2010). One of the important findings of the present study is that female patients with migraine had a higher likelihood of neuromagnetic activation in the supplementary motor area and ipsilateral sensorimotor cortices. This observation indicates that there is a spread of abnormal ictal brain activation triggered by movements. Since migraine is associated with cortical hyperexcitability, spread of abnormal ictal brain activation triggered by movements may play a key role in the cascade of migraine attacks. This observation might be critical for developing spatially targeted treatments for migraine. For example, high-frequency rTMS increase and low-frequency rTMS decrease neural excitability of the stimulated cortex (Brigo et al., 2012; Teepker et al., 2010; Minks et al., 2010). If MEG could reliably reveal the location and types of cortical dysfunction occurring during migraine attacks, all of the preventions and treatments targeted at cortical excitability (Coppola and Schoenen, 2012; Rapoport, 2011; Bigal et al., 2008) could be refined and optimized. Therefore, we consider the present study



to lay an important foundation for clinical management of migraine in the future. Though our MEG results showed that migraine was associated with a prolonged latency of motor-evoked magnetic fields and increase of neuromagnetic activation, it remains largely unknown if and how a prolonged latency of MEFs is related to increased neuromagnetic activation. One possible postulation is that a prolonged latency of MEFs has no relationship with the increased neuromagnetic activation. Specifically, the delay of motor-evoked brain responses results from white matter impairments in migraine subjects (Rocca et al., 2003) and the increased neuromagnetic activation results from cortical hyperexcitability (Bowyer et al., 2005). Another possible postulation is that migraine is associated with significant cortical dysfunction that causes a prolonged latency of MEFs and increased neuromagnetic activation. Altered cortical excitability and inhibition of neural network in patients with migraine have been reported by multiple investigators (Charles, 2009). The prolonged latency of MEFs and increased neuromagnetic activation might be the manifestation of cortical dysfunction during migraine attack. 5. Conclusion The results of the present study have demonstrated that female patients with migraine during a headache attack had delayed motor cortical activation, increased cortical activation, and a higher likelihood of neuromagnetic activation in the supplementary motor area and ipsilateral sensorimotor cortices. The findings of increased cortical activation beyond the primary motor cortex in female patients with migraine support the notion that migraine is associated with cortical hyperexcitability. The spread of abnormal ictal brain activation triggered by movements may play a key role in the cascade of migraine attacks. These findings may be useful for developing spatially targeted treatment (such as rTMS) for migraine treatment in the future. Acknowledgments The authors gratefully acknowledge the support of Department of Neurology, Nanjing Brain Hospital Nanjing Medical University. This study was financed based on a National Natural Science Foundation of China grant, grant number 81271440. The authors have indicated no financial conflicts of interest. References Aurora SK, Al-Sayeed F, Welch KM. The cortical silent period is shortened in migraine with aura. Cephalalgia 1999;19:708–12. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48:1157–68. Bohotin V, Fumal A, Vandenheede M, Gerard P, Bohotin C, Maertens DNA, et al. Effects of repetitive transcranial magnetic stimulation on visual evoked potentials in migraine. Brain 2002;125:912–22. Bowyer SM, Aurora KS, Moran JE, Tepley N, Welch KM. Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann Neurol 2001;50:582–7. Bowyer SM, Mason KM, Moran JE, Tepley N, Mitsias PD. Cortical hyperexcitability in migraine patients before and after sodium valproate treatment. J Clin Neurophysiol 2005;22:65–7. Brighina F, Palermo A, Daniele O, Aloisio A, Fierro B. High-frequency transcranial magnetic stimulation on motor cortex of patients affected by migraine with aura: a way to restore normal cortical excitability? Cephalalgia 2010;30:46–52. Brigo F, Storti M, Nardone R, Fiaschi A, Bongiovanni LG, Tezzon F, et al. Transcranial magnetic stimulation of visual cortex in migraine patients: a systematic review with meta-analysis. J Headache Pain 2012;13:339–49. Buse D, Manack A, Serrano D, Reed M, Varon S, Turkel C, et al. Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. Headache 2012;52:3–17. Charles A. Advances in the basic and clinical science of migraine. Ann Neurol 2009;65:491–8.

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