Order 1106099: migraine

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The Journal of Pain, Vol 17, No 6 (June), 2016: pp 694-706 Available online at www.jpain.org and www.sciencedirect.com

Spatial Heterogeneity of Cortical Excitability in Migraine Revealed

by Multifrequency Neuromagnetic Signals

Jing Xiang,*,y Kimberly Leiken,* Xinyao Degrauw,* Benjamin Kay,* Hisako Fujiwara,* Douglas F. Rose,*,y Janelle R. Allen,z Joanne E. Kacperski,*,y Hope L. O’Brien,*,y

Marielle A. Kabbouche,*,y Scott W. Powers,y,z and Andrew D. Hershey*,y

MEG Center, Divisions of *Neurology, and zBehavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. yDepartment of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.

Received 11, 2016. This pro 1R21NS0 Institute The auth Address r Neurolog Burnet A

1526-590

ª 2016 b http://dx

694

Abstract: To investigate the spatial heterogeneity of cortical excitability in adolescents with migraine, magnetoencephalography (MEG) recordings at a sampling rate of 6,000 Hz were obtained

from 35 adolescents with an acute migraine and 35 age- and sex-matched healthy control participants

during an auditory–motor task. Neuromagnetic activation from low- to high-frequency ranges (5–

1,000 Hz) was measured at sensor and source levels. The heterogeneity of cortical excitability was

quantified within each functional modality (auditory vs motor) and hemispherical lateralization.

MEG data showed that high-frequency, not low-frequency neuromagnetic signals, showed heteroge-

neous cortical activation in migraine subjects compared with control participants (P < .001). The alter-

ation of the heterogeneity of cortical excitability in migraine subjects was independent of age and

sex. The degree of the neuromagnetic heterogeneity of cortical activation was significantly corre-

lated with headache frequency (r = .71, P < .005). The alteration of cortical excitability in migraine

subjects was spatially heterogeneous and frequency dependent, which previously has not been re-

ported. The finding may be critical for developing spatially targeted therapeutic strategies for

normalizing cortical excitability with the purpose of reducing headache attacks.

Perspective: This article presents a new approach to quantitatively measure the spatial heteroge- neity of cortical excitability in adolescents with migraine using MEG signals in a frequency range of 5

to 1,000 Hz. The characteristics of the location and degree of cortical excitability may be critical for

spatially targeted treatment for migraine.

ª 2016 by the American Pain Society Key words: Migraine, cortical excitability, headache, high-frequency oscillations, magnetoencephalog-

raphy.

igraines are characterized by variable fre- quency, severity, duration, and headache char- acteristics, and are associated with a variety of

focal cortical dysfunction.15 Headache and associated neural dysfunction in migraine may manifest during early childhood and pose challenging diagnostic di- lemmas.16 Migraine sufferers are typically hypersensitive

July 23, 2015; Revised December 23, 2015; Accepted February

ject was supported by grant number R21NS072817 and 81420-01A1 from the National Institutes of Health, National of Neurological Disorders and Stroke. ors have no conflicts of interest to declare. eprint requests to Jing Xiang, MD, PhD, MEG Center, Division of y, MLC 2015, Cincinnati Children’s Hospital Medical Center, 3333 venue, Cincinnati, OH 45220. E-mail: [email protected]

0/$36.00

y the American Pain Society

.doi.org/10.1016/j.jpain.2016.02.009

to multiple stimuli including visual (photophobia), auditory (phonophobia), and sensory (cutaneous allodynia) stimuli during migraine attacks.12,17,34

Although it is well recognized that the clinical manifestations of migraines are heterogeneous,9,26,30

the neurophysiological mechanism underlying the heterogeneous clinical manifestations remains largely unknown. Recent reports have shown that cyclical changes of

cortical excitability play a key role in migraine at- tacks.15,36 Magnetoencephalography (MEG), a relatively new clinical modality for noninvasive assessment of functional brain activation, has been used to find that there are significant neuromagnetic abnormalities in the motor cortex of childhood migraine sufferers.13,37

There is evidence that the auditory cortex exhibits decreased activation in some childhood migraine

Xiang et al The Journal of Pain 695

sufferers.24 Reports from functional21 and transcranial magnetic stimulation (TMS)29 studies also showed that migraine subjects have impaired cortical excitability. Neurophysiological and neuroimaging reports have pro- vided ambiguous findings regarding cortical excitability. There have been reports of hyper- and hypoexcitability in a variety of brain areas including somatosensory, mo- tor, and visual cortices,6,10,27 although the cerebral mechanisms underlying the conflicting findings are unclear. The assessment of cortical excitability is typically per-

formed for 1 functional modality (eg, motor, somatosen- sory, or auditory).9,29,32,37 Despite the fact that alteration of cortical excitability plays a pivotal role in migraine, to our knowledge, no study to date has simultaneously assessed the relative cortical excitability in multiple systems. Because the identification of underlying cortical dysfunction in migraine can lead to future identification of neurophysiological biomarkers for studying migraine,10 it is necessary to determine if the alteration of cortical excitability in migraine is a hetero- geneous or homogenous change. The objective of the present study was to investigate

the heterogeneity of cortex excitability in adolescents with migraine, using an optimized paradigm specifically focusing on auditory and motor cortices. We hypothe- sized that the alterations of cortical excitability are het- erogeneous across the auditory and motor systems. The major methodological improvement upon previous studies was the quantification of the heterogeneity of cortical excitability by measuring brain activation at source levels. The main scientific innovation was the an- alyses of brain activation in a high-frequency range (up to 1,000 Hz) in migraine, with additional spatial, spectral power, and frequency descriptions, compared with con- ventional measurement of brain waveforms. Under- standing the heterogeneity of cortical excitability in migraine is important for better understanding the het- erogeneous nature of clinical migraine symptoms, and may yield a neurophysiological phenotype of headaches for personalized treatment and prevention (ie, MEG- guided normalization of cortical excitability using TMS).

Methods

Subjects Thirty-five subjects diagnosed with acute migraine (26

female, 9 male; mean age 15.2 years; SD 1.6 years; age range 11–17 years) were recruited from the Headache Center at Cincinnati Children’s Hospital Medical Center (CCHMC). Inclusion criteria were: 1) migraine with or without aura as defined in the International Classifica- tion of Headache Disorders, 3rd edition (beta version)14; and 2) no other neurological disorder. Control partici- pants were recruited to match the migraine subjects for age and sex and met inclusion criteria of: 1) healthy without history of neurological disorder, headache or brain injury; and 2) age-appropriate hearing, vision, and hand movement. Exclusion criteria for all partici- pants were: 1) presence of an implant, such as cochlear

implant devices, a pacemaker or neuro-stimulator, de- vices containing electrical circuitry, generating magnetic signals, or having other metal that could produce visible magnetic noise in the MEG data; and 2) noticeable anxi- ety (eg, expressing worry about the tests, noticeable physical trembling, or sweating), and/or inability to readily communicate with personnel operating the MEG equipment. The research protocol was reviewed and approved by the institutional review board (IRB) at CCHMC. Informed consent, formally approved by the IRB at CCHMC, was obtained from each subject before testing. The migraine subjects were evaluated for eligibility by

neurologists who specialized in headache medicine. The clinical characteristics of migraine subjects were prelimi- narily assessed with a questionnaire developed in previ- ous studies.19 The questionnaire included headache frequency, duration, severity, and information about prophylactic and acute medication.20 If migraine subjects met the criteria of the present study, a researcher would then perform a more in-depth screening process and obtain IRB-approved consent forms. MEG data from the migraine subjects were recorded during their head- ache attacks (or during episodes). Recordings were per- formed before initiation of treatment for patients who were referred to the Acute Headache Unit at CCHMC for treatment of an acute headache (from February 1, 2009 to March 1, 2015). The clinical characteristics of the subjects are shown in Table 1. All of the subjects diag- nosed with acute migraine who completed the MEG tests during their headache attack were also asked to return for a second MEG visit. Twenty-one of the 35 subjects with migraine were able to return for a follow-up MEG appointment.

Auditory–Motor Paradigm Similarly to previous reports,22,35 subjects were

instructed to press a response button immediately after the presentation of a 500-Hz square wave tone. Subjects were instructed to use the index finger that was ipsilat- eral to the ear in which the tone was played, while keep- ing other body parts still with eyes open and fixed to a target on the screen in front of them during the tests (Fig 1). A trigger from the response button was sent to the MEG system for each button press. The stimuli con- sisted of 200 trials of tones, 100 trials per ear, which were presented randomly through plastic tubes and earphones. Stimulus presentation and response recording were accomplished with BrainX software, which used DirectX technology (Microsoft Corporation, Redmond, WA).22,35

MEG Recording The MEG signals were recorded in a magnetically

shielded room (Vacuum-Schmelze, Hanau, Germany) us- ing a whole head CTF 275-Channel MEG system (VSM MedTech Systems Inc, Coquitlam, British Columbia, Can- ada) in the MEG Center at CCHMC. Before data acquisi- tion began, electromagnetic coils were attached to the nasion, and to the left and right preauricular points of

Table 1. Clinical Characteristics of Subjects

PARAMETER MIGRAINE CONTROL

Mean age 6 SD, y 15.2 6 1.6 15.3 6 1.4

Sex, female/male 26/9 26/9

Handedness, right/left 30/5 30/5

Patients with aura/without aura 8/27 N/A

Mean frequency of headache per mo 6 SD 7.4 6 3.7 N/A

Mean years of suffering from migraine 6 SD 3.6 6 2.9 N/A

Mean duration of headache 6 SD, h 9.2 6 4.8 N/A

Mean severity of headache 6 SD

(on scale: 0–10)

6.7 6 2.6 N/A

Pain type, n*

Throbbing 21 N/A

Pressure 17 N/A

Constant 9 N/A

Sharp 6 N/A

Squeezing 5 N/A

Stabbing 4 N/A

Other 3 N/A

Medications for preventive treatment before MEG tests, ny None 14 N/A

Amitriptyline 9 N/A

Divalproate 2 N/A

Levetiracetam 3 N/A

Topiramate 10 N/A

Vitamin D 4 N/A

Coenzyme Q10 12 N/A

Riboflavin 8 N/A

Abbreviation: N/A, not available.

*Participants may have more than 1 type of pain.

yMultiple drugs/nutraceuticals might be used.

696 The Journal of Pain Heterogeneity of Cortical Excitability in Migraine

each subject. These 3 coils were subsequently activated at different frequencies for measuring participants’ head positions relative to the MEG sensors. The sampling rate of the MEG recordings was 6,000 Hz. An acquisition window was set to 3,000 ms per trial, with 2,000 ms pre- trigger. Data were recorded with a noise cancellation of third-order gradients. Subjects were asked to remain still. If head movement during a recording was beyond

Figure 1. Sound cue and finger tapping paradigm. A tone is sent to the participant’s left or right ear in a randomized order. The subject is instructed to press a button on her/his left side when the tone is sent to the left ear, and press a button on her/his right side when the tone is sent to the right ear. Each tone and finger-tapping trial sends a unique signal (trigger) to the MEG system in real time, and the MEG system will record and store the unique signal to the MEG data set for analysis of auditory and movement-related neuromagnetic responses. The pretrigger baseline is designed to record background brain activity and noise.

5 mm, that data set was indicated as ‘‘bad’’ and an addi- tional recording was performed.

Magnetic Resonance Imaging Scan Three-dimensional magnetic resonance imaging was

obtained using a 3T Philips Achieva scanner (Philips Healthcare, Andover, MA). Three fiducial marks were placed in locations identical to the positions of the 3 coils used in the MEG recordings, with the aid of digital pho- tographs to allow for an accurate coregistration of the 2 data sets. Similarly to our previous reports,37 all anatom- ical landmarks were made identifiable in the magnetic resonance images.

Sensor Level Analysis To analyze time-locked neuromagnetic responses, con-

ventional averaging was applied to waveform data.13,24,35 To analyze phase-locked neuromagnetic os- cillations (not necessarily time-locked), MEG waveforms were transformed to spectrograms, as described in detail in previous reports.38,39 The spectral characteristics of MEG data were analyzed with spectrograms computed using the Morlet continuous wavelet algorithm with 600 frequency bins up to 1,000 Hz (1 kHz) from time series data.38 To measure neuromagnetic spectral power elicited by sound and finger movements, accumulated spectrograms from 100 trials for left or right tone or finger movement were computed separately. To quantify the neuromagnetic spectral power, we computed ‘‘global spectral power’’ by calculating the sum of the spectral power from all sensors over the target frequency ranges of 5 to 100 Hz and 100 to 1,000 Hz. The details of the mathematical algorithms have been described in pre- vious reports.38,39

To facilitate the measurements, we used a custom- designed program, MEG Processor, which automatically measured the mean and peak value for each frequency of the 600 bins for all MEG sensors.38,39 This approach was ideal because the entire calculation was completed objectively by an optimized work flow.24,25 The time window for quantifying spectral power at sensor levels was 0 to 200 ms for the frequency ranges of interest (5–100 Hz and 100–1,000 Hz) for auditory and movement-elicited activation. To ensure that our results were comparable with previous reports37 using different frequency resolution, all spectral power presented in this study was normalized by frequency bins. Compared with previous reports,37 one methodological improvement in this study was the removal of the spectral baseline by subtracting the spectrograms computed with pretrigger recording from auditory or motor response spectro- grams for each subject (Fig 1).

Source Level Analysis Neuromagnetic sources were localized with volu-

metric source imaging.38,39 The new method scanned each coordinate voxel.24,25 To capture the dynamic spatiotemporal activity in the brain, we applied a sliding window to the source estimation. Multiple local spheres were used for computing the magnetic

Xiang et al The Journal of Pain 697

forward solution. MEG Processor was used to localize magnetic sources.23,25 According to a previous study,35

along with the observation of spectral contour maps in the present study that showed dominant activation around the primary motor and auditory regions, the time window and frequency ranges for source estima- tion were selected as 0 to 200 ms for signals in the 2 fre- quency ranges of 5 to 100 Hz and 100 to 1,000 Hz. The highest frequency was governed by the Nyquist sampling theorem as well as floating data point error during computation.38

Quantification of the Heterogeneity of Cortical Excitability To quantitatively measure the heterogeneity of

cortical excitability, we developed a set of equations (see the following Equation [Eq] 1 and 2 for examples).

AL � MR ¼ abs ðAL � MRÞ (Eq 1)

AR � ML ¼ abs ðAR � MLÞ (Eq 2)

In the equations, A represents auditory activation; M represents motor activation; L indicates left stimulation, and R indicates right stimulation. The combination of AL indicates auditory activation evoked/elicited by left stim- ulation and the combination of MR indicates motor acti- vation evoked/elicited by right stimulation, and abs indicates absolute value. By using 2 neural systems (audi- tory vs. motor) and two hemispheres (left vs. right), we were able to obtain 6 parameters with equal number of equations: AR-AL, AR-MR, AR-MR, AL-MR, AL-ML, and MR-ML. For example, by using Eq 1, we could obtain an AL-MR value. An AL-MR value represents the differ- ences between auditory activation elicited by left sound stimulation and motor activation elicited by right finger tapping. In the present study, we used the same equation in the analyses of the MEG waveform amplitude, spectral power, and source strength.

Statistical Analysis MEG measurements were statistically analyzed with

pairwise comparisons (Student t-test) and multiple analysis of variance (ANOVA). The fixed factors were group (migraine and control groups) and age (catego- rized according to quartiles within the 11–17 range). The dependent variables were waveform amplitude, spectral power, and source strength. The odds ratio of activity in brain areas among the migraine and con- trol groups was analyzed with Fisher exact tests. The correlation between headache frequency/severity and MEG parameters (waveform amplitude, spectral po- wer, and source strength) were analyzed with the Spearman correlation. Significance was accepted at the level of P < .05 for one test. For multiple compari- sons, a Bonferroni multiple comparison correction was applied. If multiple tests were to be taken into account then the significance threshold for any one of these tests were reduced from .05 to .025 (2 parameters) or .008 (6 parameters).

Results

Clinical Characteristics As shown in Table 1, 26 of the 35 migraine subjects in

the present study were female (26/35, 74%). Thirty of the 35 migraine subjects had moderate to severe head- ache (30/35, 86%). Twenty-eight of 35 migraine subjects had bilateral headache attacks (28/35, 80%). Eight of the 35 migraine subjects had aura (8/35, 23%), the other 27 migraine subjects did not have aura (27/35, 77%). Four- teen of the 35 migraine subjects had not used any pre- ventive drug therapy (14/35, 40%); the other 21 migraine subjects used preventive drugs before MEG re- cordings (see Table 1 for details). The time between the medication intake and the MEG recording in the 21 migraine subjects was 34.2 6 14.1 hours.

Waveform Amplitude MEG waveforms recorded from the 35 migraine and

control subjects showed at least 1 response (deflection) in the bilateral auditory cortices after auditory stimula- tion and at least 1 response in the contralateral motor cortex during finger tapping. Because the first waveform peak (ie, auditory M100, motor M1) was the most consis- tent neurophysiological response among the 2 groups of subjects, the quantification of waveforms focused on the first peak after either auditory stimulation or motor finger tapping. Fig 2 shows waveforms from a migraine and a control subject. Fig 3 shows the results of the group comparisons of the MEG measurements in migraine and control subjects. An ANOVA with repeated measures re- vealed that migraine significantly affected the level of the neuromagnetic difference between the auditory and motor activation in the left or right hemisphere, in- dependent of age and sex (P < .005). The results sug- gested that cortical activation in the auditory and motor cortices in migraine subjects was heterogeneous compared with control subjects. In other words, the levels of the alteration of cortical excitability in migraine subjects were heterogeneous, occurring predominantly in either auditory or motor cortex.

Spectral Power

Power of 5 to 100 Hz

The spectrograms in the 5 to 100 Hz range showed that migraine subjects had focal increased spectral power at 0 to 200 ms. Fig 4 shows spectrograms at 5 to 100 Hz from a migraine and a control subject. Fig 5 shows the re- sults of group comparisons of the measurements of sensor-level spectral power at 5 to 100 Hz from all migraine and control subjects. An ANOVA with repeated measures revealed that migraine significantly affected the level of the neuromagnetic difference between the auditory and motor activation in the left or right hemi- sphere, independent of age and sex (P < .005). The results of spectral power at 5 to 100 Hz suggested that cortical activation in the auditory and motor cortices in migraine subjects was heterogeneous compared with control subjects.

Figure 2. MEG waveforms. Typical responses from the most significant channels of MEG waveforms show neuromagnetic activation evoked by auditory stimulation (M100 and M200) and finger movement (M1 and M2). ‘‘Migraine’’ indicates the MEG data were re- corded from a migraine subject, and ‘‘Normal’’ indicates the MEG data were recorded from a healthy control participant. Abbrevia- tion: fT, femtotesla.

698 The Journal of Pain Heterogeneity of Cortical Excitability in Migraine

Power of 100 to 1,000 Hz

The spectrograms in the 100 to 1,000 Hz range re- vealed that migraine subjects had increased spectral power at 0 to 200 ms. Fig 6 shows spectrograms at 100 to 1,000 Hz from a migraine subject and a control subject. Fig 7 shows the results of group comparisons of the measurements of sensor-level spectral powers at 100 to 1,000 Hz from all migraine and control sub- jects. An ANOVA with repeated measures revealed that migraine significantly affected the level of the

Figure 3. Group comparisons of MEG waveforms. ‘‘A’’ indicates auditory activation; ‘‘M’’ indicates motor activation; ‘‘R’’ indi- cates right stimulation; ‘‘L’’ indicates left stimulation. For example, ‘‘AR-ML’’ indicates the difference between auditory activation evoked by right sound stimulation and motor activa- tion evoked by left finger tapping. Each bar represent the mean and standard error of the values. ‘‘Migraine’’ indicates the data recorded from migraine subjects, and ‘‘Control’’ indicates the data recorded from healthy control subjects. The unit of ampli- tude is fT. *P < .005. Abbreviation: fT, femtotesla.

neuromagnetic difference between the auditory and motor activation in the left or right hemisphere, inde- pendent of age and sex (P < .0025). The results of spec- tral power at 100 to 1,000 Hz suggested that cortical activation in auditory and motor cortices in migraine subjects was heterogeneous compared with control subjects.

Source Strength

Strength of 5 to 100 Hz

MEG source analyses revealed that auditory activation in the occipital region was identified in 12 migraine sub- jects (12/35, 34%) but not in any control subjects. In addi- tion, we noted that ipsilateral motor cortex activation was found in migraine subjects (9/35) but not in control subjects. Compared with control subjects, migraine sub- jects had significantly higher odds of activation in the oc- cipital region after auditory stimulation (P < .01) and ipsilateral motor cortex during finger tapping (P < .01). Fig 8 shows magnetic source imaging at 5 to 100 Hz

from a migraine subject and a control subject. Fig 9 shows the results of group comparisons of the measure- ments of source strengths at 5 to 100 Hz from all migraine and control subjects. An ANOVA with repeated measures revealed that migraine significantly affected the level of the neuromagnetic difference between the auditory and motor activation, independent of age and sex (P < .0025). The results of source strength at 5 to 100 Hz suggested that cortical activation in the auditory and motor cortices in migraine subjects was heteroge- neous compared with control subjects. In other words, the alteration of cortical excitability in migraine subjects was spatially selective, which predominantly occurs in

Figure 4. Accumulated spectrograms at 5 to 100 Hz. The spectrograms show the spectral components between 5 and 30 Hz and be- tween 70 and 80 Hz. Compared with the healthy control (‘‘Normal’’), the migraine subject (‘‘Migraine’’) shows elevated activation (green arrows). The X-axis (horizontal) indicates latency in milliseconds; the Y-axis (vertical) indicates frequency in Hz.

Xiang et al The Journal of Pain 699

either the auditory or the motor cortex. Further analysis revealed that the level of the neuromagnetic difference between the auditory and motor activation in the same hemisphere was also significantly increased in migraine subjects compared with control subjects. This observa- tion suggests that the heterogeneity of cortical excit- ability had a hemispherical effect although the predominant factor was from the auditory and motor systems. In other words, different neural systems (audi- tory vs motor) and different hemispheres (left vs right)

Figure 5. Group comparisons of spectral power at 5 to 100 Hz. ‘‘A’’ indicates auditory activation; ‘‘M’’ indicates motor activa- tion; ‘‘R’’ indicates right stimulation; ‘‘L’’ indicates left stimula- tion. For example, ‘‘AR-ML’’ indicates the difference between auditory activation evoked by right sound stimulation and mo- tor activation elicited left finger tapping. Each bar represent the mean and standard error of the values. ‘‘Migraine’’ indicates that the data were recorded from migraine subjects, and ‘‘Con- trol’’ indicates that the data were recorded from healthy control participants. The unit of spectral power is fT (femtotesla)2/Hz. *P < .005; **P < .0025.

resulted in the heterogeneity of cortical excitability in migraine subjects.

Strength of 100 to 1,000 Hz

MEG source analyses revealed that the auditory activa- tion in the occipital region was identified in some migraine subjects (13/35, 37%) but not in control sub- jects. In addition, activation in the ipsilateral motor cor- tex was found in migraine subjects (12/35, 34%) but not in control subjects. Compared with control subjects, migraine subjects had significantly higher odds of activa- tion in the occipital region after auditory stimulation (P < .01) and ipsilateral motor cortex during finger tap- ping (P < .01). Fig 10 shows magnetic source imaging at 100 to

1,000 Hz from a migraine subject and a control subject. Fig 11 shows the results of group comparisons of the measurements of source strengths in 100 to 1,000 Hz from all migraine and control subjects. An ANOVA with repeated measures revealed that migraine significantly affected the level of the neuromagnetic difference be- tween the auditory and motor activation, independent of age and sex (P < .001). The results of source strength at 100 to 1,000 Hz suggested that the alteration of cortical excitability in the auditory and motor cortices in migraine subjects was spatially selective, which was spatially heterogeneous compared with control subjects. Even in the same hemisphere, the alteration of auditory and motor cortical excitability was spatially selective.

Neuromagnetic Correlates of Clinical Manifestations The analyses of waveform amplitude and clinical data

revealed that there was correlation between frequency

Figure 6. Accumulated spectrograms at 100 to 1,000 Hz. The spectrograms show the spectral components at 100 to 200 Hz. Compared with healthy control subjects (‘‘Normal’’), migraine subjects (‘‘Migraine’’) show elevated activation (green arrows). The X-axis (horizontal) indicates latency in milliseconds; the Y-axis (vertical) indicates frequency in Hz.

700 The Journal of Pain Heterogeneity of Cortical Excitability in Migraine

of headaches per month and the difference between auditory and motor activation in the left or right hemi- sphere (AR-ML: r = .43, P < .05; AL-MR: r = .42, P < .05). There were no significant correlations between other clinical manifestations and the measurements of wave- form amplitude. The analyses of spectral power at 5 to 100 Hz and

clinical data revealed a significant correlation be- tween the frequency of headaches per month and the difference between auditory and motor activa- tion in the left or right hemisphere (AR-ML: r = .53,

Figure 7. Group comparisons of spectral power at 100 to 1,000 Hz. ‘‘A’’ indicates auditory activation; ‘‘M’’ indicates motor activation; ‘‘R’’ indicates right stimulation; ‘‘L’’ indicates left stim- ulation. For example, ‘‘AR-ML’’ indicates the difference between auditory activation evoked by right sound stimulation and mo- tor activation evoked by left finger tapping. Each bar represent the mean and standard error of the values. ‘‘Migraine’’ indicates that the data were recorded from migraine subjects, and ‘‘Con- trol’’ indicates that the data were recorded from healthy control participants. The unit of spectral power is fT (femtotesla)2/Hz. **P < .0025.

P < .05; AL-MR: r = .52, P < .05). There were no signif- icant correlations between other clinical manifesta- tions and the measurements of spectral power at 5 to 100 Hz. The analyses of spectral power at 100 to 1,000 Hz (.1–

1.0 kHz) and clinical data revealed that there was a corre- lation between frequency of headaches per month and the difference between auditory and motor activation in the left or right hemisphere (AR-ML: r = .53, P < .025; AL-MR: r = .52, P < .025). There were no significant corre- lations between other clinical manifestations and the measurements of spectral power at 100 to 1,000 Hz. The analyses of source strength at 5 to 100 Hz and clin-

ical data revealed that there was a correlation between frequency of headaches per month and the difference between auditory and motor activation in the left or right hemisphere (AR-ML: r = .61, P < .005; AL-MR: r = .62, P < .005). There were no significant correlations between other clinical manifestation and the measure- ments of source strength at 5 to 100 Hz. The analyses of source strength at 100 to 1,000 Hz (.1–

1.0 kHz) and clinical data revealed that there was a corre- lation between frequency of headaches per month and the difference between auditory and motor activation in the left or right hemisphere (AR-ML: r = .64, P < .005; AL-MR: r = .71, P < .005). There were no significant corre- lations between other clinical manifestations and the measurements of source strength at 100 to 1,000 Hz. There were no significant differences between

migraine subjects with aura and subjects without aura in terms of waveform amplitude/latency and spectral po- wer at sensor levels. However, we observed that migraine subjects with auras had activation in the occipital region in 6 subjects (6/8, 75%), and 7 migraine subjects (7/27, 26%) without auras had activation in the occipital

Figure 8. Magnetic source imaging showing brain activation at 5 to 100 Hz. The data were recorded from a migraine subject (‘‘Migraine’’) and a healthy control participant (‘‘Normal’’). Neuromagnetic signals evoked by the sound cue and finger tapping task are localized to the primary auditory and motor cortices for the migraine subject and the control participant. However, neuro- magnetic signals are also localized to the middle occipital and the ipsilateral sensorimotor cortices in the migraine subject (green ar- rows), but not in the healthy control participant. ‘‘R’’ indicates right auditory stimulation or right finger tapping; ‘‘L’’ indicates left auditory stimulation or left finger tapping.

Xiang et al The Journal of Pain 701

Figure 9. Group comparisons of source strength at 5 to 100 Hz. ‘‘A’’ indicates auditory activation; ‘‘M’’ indicates motor activa- tion; ‘‘R’’ indicates right stimulation; ‘‘L’’ indicates left stimula- tion. For example, ‘‘AR-ML’’ indicates the difference between auditory activation evoked by right sound stimulation and mo- tor activation evoked by left finger tapping. Each bar represent the mean and standard error of the values. ‘‘Migraine’’ indicates that the data were recorded from migraine subjects, and ‘‘Normal’’ indicates that the data were recorded from healthy control participants. Because the sources are statistically deter- mined, there is no unit of measure. *P < .005; **P < .0025.

702 The Journal of Pain Heterogeneity of Cortical Excitability in Migraine

regions. Compared with migraine subjects without aura, migraine subjects with aura had significantly higher odds of activation at 100 to 1,000 Hz in the occipital

Figure 10. Magnetic source imaging showing brain activation at 1 (‘‘Migraine’’) and a healthy control participant (‘‘Normal’’). Activatio cortex are only identified in the migraine subject (green arrows), bu tory stimulation or right finger tapping; ‘‘L’’ indicates left auditory s

region (P < .02) during the finger tapping task. We also noted that migraine subjects with aura were more likely to show activation at 100 to 1,000 Hz in the ipsilateral sensorimotor region (5/8, 63%) compared with migraine subjects without aura (7/27, 26%). However, there was no statistical significance (P = .06) in terms of odds ratio. There was no significant difference between migraine subjects with aura and subjects without aura in terms of source strength. There were no significant differences between

migraine subjects who were and who were not receiving preventive drug therapy in terms of waveform ampli- tude/latency and spectral power at 5 to 100 Hz or 100 to 1,000 Hz. There was a numerical trend that preventive drug use could minimize the level of the neuromagnetic difference between the auditory and motor activation at 5 to 100 Hz (P = .063) and 100 to 1,000 Hz (P = .054), how- ever, the statistical significance did not reach the accept- able criteria. There was no statistical difference between the 2 groups in terms of odds ratio of activation of the primary motor cortex during the finger tapping tasks.

Neuromagnetic Characteristics During the No Episode State Of the 35 migraine subjects who had MEG tests during

their headache attacks (ictal MEG), 21 subjects

00 to 1,000 Hz. The data were recorded from a migraine subject n in the middle occipital region and the ipsilateral sensorimotor t not in the healthy control participant. ‘‘R’’ indicates right audi- timulation or left finger tapping.

Figure 11. Group comparisons of source strength at 100 to 1,000 Hz. ‘‘A’’ indicates auditory activation; ‘‘M’’ indicates mo- tor activation; ‘‘R’’ indicates right stimulation; ‘‘L’’ indicates left stimulation. For example, ‘‘AR-ML’’ indicates the difference between auditory activation evoked by right sound stimula- tion and motor activation evoked by left finger tapping. Each bar represents the mean and standard error of the values. ‘‘Migraine’’ indicates the data recorded from migraine sub- jects, and ‘‘Control’’ indicates the data were recorded from healthy control participants. Because the sources are statisti- cally determined, there is no unit of measure. *P < .005; **P < .0025; ***P < .001.

Xiang et al The Journal of Pain 703

completed the second MEG recording. At the time of this second visit, 18 of the 21 subjects were not having head- ache attacks (interictal, headaches were well controlled), and the other 3 subjects were still having headache at- tacks (headaches were not well controlled). There were no significant differences between the 2 groups of pa- tients in terms of the second MEG measurements, prob- ably because of the limited number of subjects who still had headache attacks in our follow-up MEG tests. Comparisons of MEG data from headache-free subjects and the control subjects showed that there were no sig- nificant differences between headache-free subjects and control subjects in terms of waveform latency/amplitude and spectral power (P > .05). However, comparisons of the second MEG measurements (interictal MEG) with the first MEG measurements (ictal MEG) from the same group of migraine subjects revealed that there were sig- nificant differences between the 2 MEG measurements in terms of latency and amplitude of MEG responses (P < .01), spectral power (P < .005), and source strength (P < .002). An ANOVA with repeated measures revealed that headache attacks significantly affected the level of the source strength difference between the auditory and motor activation in the left or right hemisphere, in- dependent of age and sex (P < .01).

Discussion Building on previous reports,13,38,39 the present study

analyzed cortical excitability with waveform amplitude, spectral power, and source strength. We used the 3 methods in the present study because each method has its own strength. The measurement of waveform amplitude mainly reveals time-locked brain activation, and the assessment of spectral power in accumulated spectrograms mainly reveals phase-locked oscillatory

activation.39 However, waveform and spectral analyses are at sensor levels with limited information about the spatial location; therefore, source imaging was used to quantify the spatial heterogeneity.39

The results of the present study provide new evidence that cortical excitability in migraine subjects is signifi- cantly altered compared with age- and sex-matched con- trol subjects during adolescence. That is, typically cortical excitability is relatively consistent across the left and right hemisphere, as well as across motor and auditory modalities. However, in migraine subjects, cortical excit- ability varies on the basis of modality and hemisphere. The results also indicate that the measurements of source strength revealed more abnormalities than that of the conventional measurements of waveform amplitudes. One possible explanation is that the measurements of waveform amplitudes were at the sensor level, which might be significantly affected by noise (eg, environ- mental and subject noise). However, the measurements of source strength spatially filters any noise. We postu- late that analyses of source strength had fewer con- founding factors than those of the analyses of waveform amplitude. Therefore, analyses of MEG signals at source levels may be the optimal direction for the future MEG study of migraine. One of the main findings of the present study was the

significant elevation of the difference between auditory and motor activation in migraine versus control subjects. The abnormalities were prominent in the source data. The neuromagnetic difference between the auditory and motor activation suggests that the relative activa- tion in the auditory and motor cortices was increased in migraine compared with control subjects. This finding is important because it may explain some conflicting re- sults in previous reports.10 Specifically, many previous re- ports using TMS6,8 and transcranial direct current stimulation1,33 have shown alteration of cortical excitability in migraine subjects. However, it remains unclear if migraine is associated with hyper- or hypoexcitability in the cortex.10 According to our data, cortical excitability in migraine subjects was due to het- erogeneity; that is cortical hyperexcitability might be observed in 1 modality (eg, motor), but not in another modality (eg, auditory) in some subjects. Intracortical inhibitory and excitatory networks in the brain caused by the regional cortical excitability changes,5,11,28 may cause some brain areas to appear hyper- and hypoexcitable. The study of high-frequency brain activation in

migraine is still new37 because many previous reports focused on aberrant low-frequency brain activation in migraine.4 The present study provides evidence that the relative activation of high-frequency signals in migraine sufferers is significantly altered compared with in control subjects. This observation is significant because recent advances in neuroscience suggest that synaptic specialization turns interneuron networks into gamma-frequency oscillators.3 Specifically, the origin of high-frequency signals may be generated by GABAergic cortical interneurons. Consequently, the hyperactivation may indicate an imbalance among excitatory and

704 The Journal of Pain Heterogeneity of Cortical Excitability in Migraine

inhibitory cortical circuits that could predispose migraineurs to periodic headache attacks.3,31 Of note, high-frequency oscillatory patterns may shed a light on pathogenesis of migraine. The frequency dependent changes of auditory and

motor activation in migraine subjects compared with control subjects have not previously been reported. Although low- and high-frequency signals could reveal the same abnormalities, the P values from high- frequency signals appeared to be higher than that of the low-frequency signals in at least 1 parameter. To our knowledge, this is the first study of relative changes of the auditory and motor systems in low- and high- frequency ranges in adolescents with migraine using MEG. Although the cerebral mechanisms underlying the differences remain unclear, increased relative activa- tion might be a result of cortical hyperexcitability.6,7,31 It seems that different frequencies may favor different types of connections and/or different spatiotemporal levels of information integration. Specifically, low- frequency signals might involve many groups of neurons over large brain areas, whereas high-frequency signals with short duration time windows might be better suited to local, neighboring cortico–cortical interactions. Because cortical excitability is the target of new treat- ments,4 the finding of frequency dependent cortical al- terations in migraine might be useful in the selection of spatial targets for treatment. MEG study of cortical excitability may play an important role in developing better and more effective therapeutic interventions for migraine in the future.18

The finding of enhanced neuromagnetic differences among auditory and motor activation in the left and right hemispheres is relevant to clinical management of pediatric migraine for several reasons. First of all, the enhanced neuromagnetic differences among auditory and motor activation in the left and right hemispheres are new biomarkers for assessing the abnormality of cortical excitability, which is different from the conven- tional measurements of waveforms showing neural re- sponses to auditory or motor tasks.13,24 MEG is a noninvasive technology that can be used to quantify these neuromagnetic differences noninvasively and safely. Second, the enhanced neuromagnetic differences among auditory and motor activation in the left and right hemispheres indicate that the alteration of cortical excitability in migraine is heterogeneous or focal. Consequently, clinical treatment, such as TMS, may selectively target the affected region or functional neural network, which may lead to better clinical outcomes.15 In other words, this finding may be very important in developing spatially targeted therapeutic interventions for migraine in the future.8,30 Third, the measurements of auditory and motor functions in the pediatric populations imply that the evaluation of a single functional modality (eg, auditory or motor) may not be appropriate for evaluating migraine biomarkers. Instead, it is important and feasible to assess multiple functional modalities (eg, auditory, motor, etc) to pinpoint the impaired neural system. Consequently, we may use the MEG data

to neurophysiologically phenotype migraines so as to better diagnose and treat migraine patients, who typically have heterogeneous clinical manifestations. Although it remains unclear why there are heterogeneous impairments in the auditory and motor system, the variation of neuromagnetic abnormalities among subjects may allow us to phenotype migraines, which may eventually lead us to more individualized prevention and treatment strategies and better clinical outcomes. We noted that the difference between auditory and

motor activation in the left or right hemisphere showed the most significant changes. One reasonable postula- tion is that the heterogeneity of cortical excitability re- sulted from different functional systems (auditory vs motor) and different hemispheres (left vs right). Accord- ing our data, different functional systems play a major role in the heterogeneity of cortical excitability, because the difference between auditory and motor activation was consistently identified in waveform, spectral, and source analyses. The increase of the difference between auditory and motor activation likely resulted from the se- lective elevation of cortical excitability in either auditory or motor cortex. Our results are consistent with previous reports.2 Aygul and colleagues have reported that left- handedness and left-dominant eyes were not signifi- cantly correlated with migraine in women.2 In men, the incidence of left-handedness and left-eye dominance was significantly higher in migraine subjects than in con- trol subjects.2 Because there were only 5 left-handed migraine subjects in the present study, the correlation between hemispherical lateralization and the MEG mea- surements is debatable. However, we consider the hemi- spherical variation support for the heterogeneity of cortical abnormalities in migraine. No significant difference was observed in MEG mea-

surements of patients who were receiving preventive drug therapy versus those who were not. This result might have been because the time between medication intake and the MEG recordings was relatively long (34.2 6 14.1 hours) in the present study. Consequently, the effect of medications on neuromagnetic activation might have already subsided. In addition, we consider that if a preventive drug normalized the cortical excit- ability for a patient, their diagnosis might have improved so greatly as to yield their ineligibility in the study. There- fore, we expect that patients who were still experiencing severe enough migraines likely benefited more modestly from preventative medication, as reflected by their MEG recordings. The neuromagnetic improvements from episode period (ictal) to no-episode period (interictal) re- cordings indicates that the elevated heterogeneity of cortical excitability during episodes can be decreased outside of headache attacks. There was no difference be- tween migraine and control subjects during the interictal period, which suggests that cortical excitability can re- turn to normal in patients with migraine. These observa- tions are consistent with previous reports.37

The correlations between the elevations of the hetero- geneity of cortical excitability and the frequency of headache attacks are intriguing. It seems that the

Xiang et al The Journal of Pain 705

variation of headache frequency is resultant from the heterogeneity of cortical excitability in various brain re- gions. We postulate that the heterogeneity of cortical excitability in migraine plays a key role in the heteroge- neous nature of migraine clinical symptoms. It would be interesting to use neuromagnetic signatures of the het- erogeneity of cortical activation to neurophysiological phenotype of headaches for personalized treatment and prevention in the future. The present pilot study has some limitations. First, the

low migraine sample size may make interpretation of re- sults more difficult. For example, because only 8 of the subjects with migraine had aura (Table 1), neuromag- netic difference between migraine with and without aura cannot be conclusively determined. Similarly, neu- romagnetic differences between treatment-controlled and treatment-uncontrolled requires more subjects in our follow-up assessments. The present study provides evidence supporting increased cortical excitability in migraine compared with control subjects, but how these neural signatures of migraine differ from those of epi- lepsy remains unknown.36,37 Because the present study focused on the auditory and motor systems, the spatial

information leading to emphasis on heterogeneity is limited to the 2 functional modalities. Therefore, it is necessary and important to increase the number of migraine subjects to generalize conclusions for all migraine patients in clinical practice in the future.

Conclusions The results of the present study provide evidence that

alteration of cortical excitability in the auditory and mo- tor systems in migraine is heterogeneous and spatially se- lective. The heterogeneity of cortical excitability resulted from functional modalities (auditory vs motor) and hemi- spherical lateralization (left vs right). It is also frequency dependent, which might be related to the modulating effects of local and global neural networks at different frequencies. The finding of significant correlations be- tween degree of heterogeneity and clinical headache frequency suggests that MEG measurements of the het- erogeneity of cortical excitability may play a key role in developing spatially targeted treatment for normalizing focal cortical excitability for reducing migraine headache attacks in the future.

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