Headache ISSN 0017-8748


C 2007 the Authors doi: 10.1111/j.1526-4610.2007.00853.x
Journal compilation 
C 2007 American Headache Society Published by Blackwell Publishing

2007 Harold G. Wolff Award Winner

Brainstem Dysfunction in Chronic Migraine as Evidenced
by Neurophysiological and Positron Emission
Tomography Studies∗
Sheena K. Aurora, MD; Patricia M. Barrodale, RN; Reda L. Tipton; Ani Khodavirdi, PhD

Background.—The pathophysiology of chronic migraine (CM) is not fully understood. We aimed to examine
transcranial magnetic stimulation (TMS) indices of cortical excitability in patients with CM and also performed
PET studies to ascertain if there were any areas of activation and inhibition for possible correlation.
Methods.—Excitability of the cortex was assessed by a reliable parameter of magnetic suppression of perceptual
accuracy (MSPA) profiles using transcranial magnetic stimulation in 25 patients with CM. Of these 10 patients were
also studied with (18 F-FDG PET) scans.
Results.—MSPA demonstrated decreased inhibition in CM compared to normal controls and episodic migraine.
The percentage of letters reported correct at 100 ms was 84.37 for CM compared to 19.14 for normal controls and
57.41 for episodic migraine. The PET evaluation in 10 subjects demonstrated increased cerebral metabolism in
areas of in the brainstem compared to the global flow. There were also decreased areas of cerebral metabolism in
the medial frontal and parietal as well as the somatosensory cortex.
Conclusions.—Patients with CM appear to be characterized by reduced visual suppression correlating with high
cortical excitability. In a cohort of these subjects there was brainstem activation and inhibition in certain areas of
the cortex suggesting a potential dysfunction in the inhibitory pathways.
Key words: chronic migraine, hyperexcitability, positron emission testing, transcranial magnetic stimulation

(Headache 2007;47:996-1003)

Headache on a daily or a near daily basis occurs in
about 5% of the general population.1 Chronic daily
headache (CDH) was2 a descriptive term used for
a heterogeneous group of conditions, which includes
headache on a daily or almost daily basis as a common
feature. The newly accepted International Headache
From the Swedish Headache Center, Seattle, WA, USA (Drs.
Aurora, Barrodale, and Ms. Tipton); Neurosicence Division,
Advanced Bionics, Valencia, CA, USA (Dr. Khodavirdi).
Address all correspondence to Dr. Sheena Aurora, Swedish
Headache Center, 1101 Madison, 200, Seattle, WA 98104, USA.
∗
This article is the winner of the 2007 Harold G. Wolff Award.
Accepted for publication April 19, 2007.
Society classification of daily headache initially pro-
posed by Silberstein and colleagues3 has the advan-
tage of differentiating the working criteria for clinically
distinct phenomena: chronic tension type headache
(TTH); new daily persistent headache (NDPH); and
hemicrania continua and chronic migraine (CM).4
Within this classification scheme problems with defini-
tion and classification of CM with relevance to clinical
practice have been identified and recent studies have
proposed a new definition for the more prevalent form
of CM.5
In most patients CM evolves from episodic mi-
graine (EM). The underlying mechanisms of CM
are not well known, but medication overuse is im-
plicit in the popular term “transformed migraine.”6

996
Headache
Routine clinical imaging for typical CM is usually nor-
mal, with no evidence of structural abnormality in
the presence of a normal neurological examination.7,8
There is, however, an increasing body of research ev-
idence on the involvement of nociceptive pathways
in CDH and migraine. The first reports came from
Raskin and colleagues,9 who observed a migraine-like
headache developed in patients with electrode implan-
tation in the periaqueductal gray (PAG). Recently the
rostral brainstem has been identified as being specif-
ically involved in migraine.10-13 The influence of the
PAG on the trigeminovascular nociception has also
been studied using neurophysiological studies. Using a
cat model, Knight and Goadsby14 stimulated the ven-
terolateral part of the PAG and demonstrated a re-
duction in evoked trigeminal neuronal activity infer-
ring that the PAG was involved in inhibition of facial
pain. Consistent with this animal work, we have pre-
viously demonstrated changes in the same anatomical
regions of humans with CM. In patients with CDH,
we noted a positive correlation between the duration
of illness and the increase in MRI index of tissue iron
levels in PAG.15 With this study we aimed to study the
metabolism of the brain with particular attention to
the brainstem in CM using positron emission testing
(PET). Neuroimaging with positron emission tomog-
raphy has shed light on the genesis of 2 of the most
important headache syndromes, documenting activa-
tion in the midbrain and pons in migraine16 and in the
hypothalamic gray in cluster headache (CH).17,18
We also aimed to study the neurophysiological ef-
fects of the brainstem activation on the cortical path-
ways. Although progress is clearly being made in un-
derstanding the long-term effects of CM on the brain-
stem, relatively little attention has been paid to the
question of how pathophysiological mechanisms in the
cortex—which are well established for EM-–operate in
patients with CM. Three a priori possibilities are distin-
guishable: first, attacks of CM arise through additional
pathophysiological mechanisms brought about by, ie,
exposure to sustained large doses of analgesics; sec-
ond, CM shares pathophysiological mechanisms with
standard migraine; third, some combination of addi-
tional and shared mechanisms is responsible for CM.
Recent advances in noninvasive techniques for
studying components of migraine pathophysiology
997
permit straightforward examination of the second pos-
sibility outlined above. In standard migraine, we19 and
others20,21 have used a variety of transcranial magnetic
stimulation protocols to adduce converging evidence
for functional cortical hyperexcitability in migraine.
One technique, termed magnetic suppression of per-
ceptual accuracy (MSPA) is an objective and reliable
way of demonstrating excitability differences between
migraine patients and controls.22 In the MSPA proto-
col, participants see a series of 3-letter trigrams flashed
briefly on a computer screen. Each trigram is followed
by a short interval of 40-190 ms, then a single magnetic
pulse is delivered by a stimulation coil held against the
occipital skull. In normal participants, plots of MSPA
data (henceforth MSPA profiles) exhibit a characteris-
tic U-shaped function; accuracy of reporting the letters
is good at short (40 ms) and long (190 ms) intervals,
but no better than chance for medium (100 ms) inter-
vals. The cellular basis for suppression of perception at
the 100 ms interval is likely to be the preferential acti-
vation of inhibitory neurons by a high-intensity TMS
stimulus.23 Using MSPA we have previously demon-
strated preliminary evidence of a spectrum of illness
where CM patients had reduced visual suppression.24
In this paper we further confirm decreased inhibition
and therefore hyperexcitability of the occipital cortex
in migraine and also an activation of the brainstem as
measured by blood flow in a subset of these patients.
METHODS
Participants.—Twenty-five patients recruited who
had CM with or without medication overuse using the
revised proposal of the new International Headache
Society classification (IHS 2004). The diagnosis was
confirmed by a prospective electronic baseline diary.
Patients who had a history of seizures, or any im-
planted medical device (eg, a pacemaker) were ex-
cluded. All participants had a normal neurological ex-
amination at the time of study. None of the participants
was taking preventive drugs as well as drugs known25
to alter central nervous system excitability (sedatives,
hypnotics, anticonvulsants or β-blockers) for at least
4 weeks prior to the study. Analgesic and abortive
medications were permitted during this 4-week period.
None, however, were taken in the 48-hour period prior
to the study except for analgesics in the CM group.
998
Studies in EM and CM patients were performed in
the interictal period with at least 48 hours between the
previous and next migraine attack. All studies were
approved by Western Institution Review Board.
Apparatus.—All eligible participants underwent oc-
cipital cortex stimulation using the Magstim 200 (The
MagStim Company Ltd, Whitland, Wales, UK). A 90-
mm circular coil was used, which has 14 turns giving a
peak magnetic field strength of 2 Tesla and 530 V/m of
peak electric field strength.
Procedure: MSPA.—Stimuli.— Visual target stim-
uli consisted of low contrast letter trigrams presented
centrally within a frame. The letters were presented
in upper case Arial 48-point font. The presence of a
frame helped equalize any crowding effect on the let-
ters and, therefore, also improved their legibility.26 The
letters used were chosen from a subset of letters of
approximately equal legibility.27 The letter trigrams,
within the frame, subtended 1.21◦ × 0.55◦ of visual
angle when viewed from a distance of 175 cm. There
was no color contrast between the trigrams and the
background: they differed only on a gray scale. Vi-
sual stimuli were presented for short durations (30-
250 ms) on a Gateway 2000 monitor and PC, running
SuperLab (Cedrus Corp., Phoenix, AZ, USA) soft-
ware. For each trigram presented, participants were
asked to verbally report the letters in the correct or-
der, which was then recorded by an experimenter.
The participants were asked to say “blank” or “don’t
know” if they were unaware of a letter at a specific
position.
Phase 1—Practice.— Before magnetic stimulation
began, participants completed a series of practice tri-
als. The first 3 trigrams were presented for 250 ms to
familiarize participants with the stimuli. Participants
then completed 10 practice trials in which the trigrams
were presented for 30 ms. If participants were unable
to report the letters accurately by the end of this ses-
sion, the practice trials were rerun to ensure that par-
ticipants were familiar with the procedures and were
able to accurately perceive the stimuli.
Phase 2—Time Course of Suppression.— In Phase
2, participants were presented with 54 trials in which
the letter trigrams were followed at a variable interval
(the stimulus onset asynchrony, SOA) by the magnetic
pulse. Six SOAs were tested: 40, 70, 100, 130, 160, and
July/August 2007
190 ms, with participants completing 9 trials at each
SOA. The order of presentation of trials was random-
ized for each participant. The intensity of the TMS
pulse was set at 75% of maximum stimulator output
for this phase of testing. Throughout, an interval of
at least 5 seconds between successive magnetic pulses
was observed. Participants responded verbally by try-
ing to name the letters in the order that they were
presented.
PET Scans.—18F fluoro-deoxyglucose positron
emission test (18 F-FDG PET) was performed for 10
of the 25 CM patients with an interval of at least 30
days. All scans were performed in the interictal pe-
riod with the last reported migraine being at least 24
hours prior. One subject did report a migraine in the
6 hours following the PET scan. All patients received
approximately 370-MBq 18 F-FDG and were allowed
to rest in a dimly lit room for approximately 45 min-
utes. Next, PET scanning of the brain was performed
under standard resting conditions in a quiet, dimly lit
room. FDG PET scans were performed with an Alle-
gro PET scanner (Philips, Amsterdam, Netherlands)
in 3-dimensional mode with RAMLA reconstruction
and standard attenuation correction. Attenuation cor-
rection was performed with a transmission scan using
a Cesium 137 source. Images were reconstructed by
3D RAMLA iterative technique through a 128 × 128
pixel image matrix (pixel size 2.0 × 2.0 mm2 ).
Images were reviewed by 1 nuclear medicine
physician with additional training in neurologic PET
imaging. The nuclear medicine physician was blinded
to clinical information. A Sun workstation (Sun Mi-
crosystems Inc., Santa Clara, CA, USA) was used for
visual image analysis. Automated analysis was used
with the 3-dimensional stereotactic surface projections
(3D-SSP) program (Neurostat, MI, USA). This pro-
gram has been described previously in detail and has
been evaluated for clinical and scientific use for anal-
ysis of PET and SPECT brains.28-31
Rotational alignment and centering of each
brain scan were performed in 3 dimensions fol-
lowed by spatial standardization along the anterior
commissure-posterior commissure line. Linear scaling
and nonlinear warping of each dataset were performed
to adjust each individual brain to a proportional grid
system, proposed by Talairich and Tournoux, resulting
Headache
in a standardized image set with a uniform voxel size
of 2.25 mm.32
Approximately 16,000 surface pixels along the sur-
face of the brain and including along the mid-sagittal
plane, reflected the metabolic activity with an average
depth of 13.5 mm. All pixels were normalized to the
average global pixel value. The resulting projections
for each individual and for the summed group were
compared to a global cerebral metabolism.
RESULTS
MSPA Profiles.—An average of MSPA profiles for
CM group are shown in Figure 1 and are compared to
MSPA profiles for normal controls and EM. For each
participant, the percentage of correctly reported let-
ters at each SOA was calculated. These percentages
were then submitted to standard analysis of variance,
with 3 levels of diagnosis (C, EM, CM) as a between-
subjects factor, and 6 levels of SOA (40, 70, 100, 130,
160, 190 ms) as a within-subjects factor. There was
a significant interaction between diagnosis and SOA,
reflecting the difference in MSPA profiles evident in
Figure 2 (F[2,34] = 71.67; P < .001). In order to exam-
ine the degree of visual suppression further across the
Magnetic Suppression of Perceptual Accuracy
100
80
Percentage correct
60
40
20
0
40
Fig 1.—Magnetic suppression of perceptual accuracy profiles by diagnostic group, separated by plot symbol. SOA is stimulus onset
asynchrony, the time in milliseconds between the appearance of the letter trigram and the delivery of the TMS pulse. C = controls;
EM = episodic migraine; CM = chronic migraine. Bars show standard errors.
999
3 groups, a suppression index score was calculated for
each participant as follows (maximum accuracy – mini-
mum accuracy)/maximum accuracy. This index may be
regarded as an estimate of the deepness/shallowness of
the typically U-shaped MSPA profile for each patient.
Index scores were submitted to standard analysis of
variance with 3 levels of diagnosis (C, EM, CM) as the
single between-subjects factor. There was a significant
effect of diagnosis: the suppression index was largest
in the C group, and smallest in the CM group, with
the EM group falling in between (F[2,34] = 85.395;
P < .001). All pairwise differences between diagnostic
groups were also significant by post-hoc Tukey’s HSD
tests.
PET Results.—The mean scores for cerebral
metabolism are shown in detail in the Table. There was
increase in the cerebral metabolism in the pons (0.793)
compared to global cerebral metabolism (0.037) (P <
.01). There were also areas of increased metabolism in
the right temporal cortex (0.589) compared to global
metabolism (0.037) (P < .01) (Fig. 3). There were areas
of decreased metabolism in several areas of bilateral
medial frontal (and parietal as well as the somatosen-
sory cortex [details in the Table]) (P < .1) (Fig. 3).
Reduction in cerebral metabolism was also seen
*
*
* *
* * * C
*
EM
CM
* p<.001
70 100 130 160 190
SOA (ms)
1000
Suppression Index
1.0
0.8
Suppression Index
0.6
0.4
0.2
0.0
Control
Mean of Maximum correct - Minimum correct / Maximum correct
Fig 2.—Suppression index for individual patients. (Note: no standard error bars for controls and episodic migraine because of smaller
n’s and more homogenous groups).
in bilateral caudate nuclei compared to global
metabolism (details in the Table) (P < .1). There was
no statistical significance for the increased metabolism
in frontal and visual cortices. Decreased metabolism
was seen in the cerebellum, anterior, and posterior
cingulate cortices but this was also not statistically sig-
nificant (details in the Table and Figs. 4 and 5).
COMMENTS
In previous work we have demonstrated a signifi-
cant difference in MSPA profile between EM patients
(with aura) and matched controls22 as well as prelimi-
nary evidence in CM.24 The results we report in this pa-
per both confirm and extend this previous finding. We
continue to demonstrate that CM patients have MSPA
profiles that are shallower again than EM patients-–
Figure 1 demonstrates clearly that virtually no sup-
pression of perception takes place in these patients.
Statistical analysis of a suppression index reveals that
this difference is robustly significant. These results of
lack of visual suppression and, therefore, reduced in-
hibition in CM are confirmed by imaging studies of
July/August 2007
Episodic Migraine Chronic Migraine
decreased metabolism by PET studies. The reduction
in cerebral metabolism in medial frontal and parietal
as well as somatosensory cortices may infer that nor-
mal inhibitory capacity of the cortex is reduced.
Previous PET techniques have used O15 to demon-
strate increase in blood flow in the pons in sponta-
neous16 and glyceral trinatrate induced migraine.33
The 18 F-FDG technique is a more robust way of as-
sessing activation since it has the advantage of di-
rectly studying metabolism instead of blood flow. In
this study we confirm the activation demonstrated in
the pons in EM. Contrary to previous PET studies in
migraine we did not see activation in the cingulate cor-
tex. The reason for this is that none of the PET studies
were performed during active migraine but were per-
formed in the interictal period. The finding of activa-
tion in the pons despite being in the interictal period
may be because of chronicity of the disorder in our
patient population.
A compelling explanation for these converging re-
sults is that cortical excitability is raised still further
in CM patients as compared to EM patients. Animal
Headache 1001

Table.—Regional Average of Cerebral Metabolism

Brain Region Mean SEM P value Brain Region

PRT-R 0.1854 0.2106 Parietal

PRT-L 0.1689 0.2232 CTX
TMP-R −0.5116 0.1903 P < .05 Temporal
TMP-L −0.1589 0.2113 CTX
FRT-R −0.1879 0.161 Frontal
FRT-L −0.0424 0.1825 CTX
OCT-R −0.5638 0.2928 Occipital
OCT-L −0.5359 0.3404 CTX
PCING-R 0.0726 0.1874 Posterior cingulate
PCING-L 0.0197 0.1615 CTX
ACING-R −0.0071 0.2033 Anterior cingulate
ACING-L −0.0979 0.2407 CTX
MFRT-R 0.4388 0.1482 P < .01 Medial frontal
MFRT-L 0.2649 0.159 P = .06 CTX
MPRT-R 0.8065 0.2022 P < .01 Medial parietal
MPRT-L 0.6784 0.2183 P < .01 CTX
SMC-R 0.779 0.1558 P << .01 Somatosensory
SMC-L 0.734 0.1795 P << .01 CTX
VC-R −0.2352 0.27 Visual
VC-L −0.1845 0.4355 CTX
CAD-R 0.7983 0.1601 P << .01 Caudate
CAD-L 1.1368 0.3217 P << .01
CBL-R 0.2465 0.514 Cerebellum
CBL-L 0.3443 0.4505
VER-R −0.3404 0.2943 Vermis
VER-L −0.324 0.3763
HEMI-R −0.2392 0.1281 Cerebral
HEMI-L −0.0499 0.1047 Hemispheres
PNS −0.9278 0.2962 P < .01 Pons
GLB −0.0366 0.0114
CTX −0.0321 0.0702

Fig 3.—Regional metabolism as compared to global meta-

bolism.

models suggest strongly that increases in cortical ex-

citability, brought about by manipulation of intracor-
tical inhibitory network activity, predispose cortex to
pathophysiological activity.34 It is plausible, therefore,
to argue that CM patients may be exceptionally sus-
ceptible to external or intrinsic triggers of migraine,
precisely because of their high cortical excitability. The
frequency of attacks is thus high.
We recognize limitations in this study in that it is a
cross-sectional study of cerebral metabolism. We are
in the process of doing follow-up PET scans on 6 of

Fig 4.—Positron emission testing scan decrease in regional metabolism.

1002
Fig 5.—PET scan increase in regional metabolism.
the 10 individuals following sham and active occipital
nerve stimulation. We will study regions of activation
and correlate the findings with the headache diaries.
We hope that some patients as a result of the treat-
ment35 may revert to EM and we will therefore then
be able to demonstrate differences in EM and CM.
The second limitation is a lack of controls in our study
with the 18 F-FDG PET. However, this technique is well
established for studying several disorders28,30 and sim-
ilar findings of pontine activation have been noted in
EM.
Nonetheless, the robust statistical significance and
the consistency of our neurophysiological findings
with previous work permit the formulation of some in-
triguing research questions for the future. First, what
can account for the very high excitability of CM cortex
observed here? One interesting hypothesis is that of
a vicious circle between brainstem and cortex. Expo-
sure to repeated attacks and sustained doses of anal-
gesics appears to result in brainstem changes as pa-
tients progress from EM to CM.15 If these brainstem
changes also upregulate cortical activation, they will
tend to increase attack frequency and hence analgesic
consumption. Second, it will be of interest to develop
longitudinal studies of the mechanisms by which EM
may transition into CM and vice versa after treatment.
Some preliminary work along these lines has already
been reported: brain stem changes in CM appear to
resolve after effective treatment.36 A complete pic-
ture of brainstem–cortex relationships in CM, over the
evolution of the disorder, should be the goal of inves-
tigators in this area: we feel that the goal is attainable
with the appropriate techniques of both neuroimag-
ing and TMS-based functional studies as reported
here.
Conflict of Interest: Dr. Khodavirdi is an employee of
Advanced Bionics.
July/August 2007
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