Interictal Dysfunction of a Brainstem Descending
Modulatory Center in Migraine Patients
Eric A. Moulton1,2, Rami Burstein3, Shannon Tully1, Richard Hargreaves4, Lino Becerra1,2,5, David
1P.A.I.N. Group, Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, United States of America, 2Department of Psychiatry,
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3Anaesthesia & Critical Care, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, Massachusetts, United States of America, 4Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America,
5Department of Radiology, Athinoula Martinos Center for Bioengineering, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United
States of America
Background: The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals
associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal
brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks,
either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could
play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an
attack (i.e. the interictal phase).
Methods and Findings: Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli
in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41uC
and noxious heat (pain threshold+1uC). Stimuli were either applied to the forehead on the affected side (as reported during
an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested
corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain
modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed
significantly greater NCF activation in control subjects than the migraine patients.
Conclusions: Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or
enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a
diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the
evaluation of therapies for migraine.
Citation: Moulton EA, Burstein R, Tully S, Hargreaves R, Becerra L, et al. (2008) Interictal Dysfunction of a Brainstem Descending Modulatory Center in Migraine
Patients. PLoS ONE 3(11): e3799. doi:10.1371/journal.pone.0003799
Editor: Hiroaki Matsunami, Duke Unviersity, United States of America
Received September 15, 2008; Accepted November 6, 2008; Published November 24, 2008
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public
domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This study was financially supported by NIH/NINDS grants to David Borsook (R01NS056195-02) and Rami Burstein (R01NS051484-04), and by an
unrestricted grant from Merck and Co. These financial sponsors did not have a direct role in this study, and did not participate in the preparation of this
Competing Interests: DB, RB, and LB serve as consultants for Merck & Co., Inc.
* E-mail: email@example.com
Defects in brainstem descending modulatory circuits may
contribute to the onset of migraine, based on structural changes
[1,2] and functional abnormalities in brainstem areas during
migraine attacks [3–5]. Enhanced responses in nociceptive spinal
and trigeminal neurons could result from these abnormalities, which
high levels of descending facilitation [7,8]. In migraine, such
hyperexcitability could lower the threshold of nociceptive neurons
in response to meningeal inputs. If dysfunctional pain modulatory
circuits exist in migraineurs, we hypothesized that functional changes
should be evident in interictal (i.e. not experiencing an attack)
migraine patients. Unlike previous studies of functional brainstem
abnormalities in migraine, this study was able to directly compare
migraine patients with healthy subjects due to the absence of ongoing
migraine pain. Our results indicate that brainstem nucleus
cuneiformis (NCF) is hypofunctional in migraine patients, possibly
contributing to hyperexcitability of trigeminovascular neurons in
migraineurs by either reduced descending inhibition or enhanced
We compared brainstem responses to thermal stimuli in migraine
patients when they were not having an attack and in healthy age-
gender-matched control subjects. Until now, no study has provided
direct evidence for specific functional changes that take place in the
brainstem during the interictal migraine period. The major finding of
thisexperiment was NCF hypofunction in interictal migraine patients
relativeto controls in responseto perceptuallysimilarthermal stimuli.
NCF has previously been related to sensory modulation in animals
[9–13] and humans [14–16]. Abnormal functioning during the
interictal state provides further evidence that an altered endogenous
system contributes to migraine pathophysiology.
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Migraine patients (9 females, 3 males; 42?2+/211?7 years old)
were free of neurological and other sensory dysfunctions, although
two patients were taking antidepressants. The patients were
selected by Dr. Burstein based on the criteria that they: (1) had
acute intermittent migraine as defined by the International
Headache Society (,14 attacks/month) and (2) had demonstrable
allodynia during migraine attacks. For those patients taking daily
medications (e.g., pre-emptive as opposed to medications to abort
the attack), patients abstained from taking their migraine
medications (Table S1) for one dosing interval prior to their
scheduled scan session. Age- and gender-matched healthy subjects
(9 females, 3 males; 42?3+/211?9 years old) were also tested. This
study was approved by the McLean Hospital Institutional Review
Board, and met the scientific and ethical guidelines for human
research of the Helsinki Accord (http://ohsr.od.nih.gov/guidelines/
helsinki.html). All patients and subjects provided written informed
consent to participate in this study.
Subjects were tested 7–10 days after their last attack, and were
apparently not in the throes of a new migraine attack. Though
patients were not surveyed days after their scan, the possibility that
they could have an imminent impending attack seems unlikely for
the following reasons: (1) no sensory differences were detected
between the migraine and healthy subjects in this study; (2) the size
of our interictal migraine group reduces the likelihood that the
majority of these episodic migraine patients were about to have an
attack, as attacks were relatively infrequent in this subject pool (,8
attacks/month); and (3) as part of another ongoing migraine
imaging study, the patients were told to call us during their next
migraine attack to schedule an impromptu imaging session, but
did not call within the week following their scan. The ongoing
migraine imaging study will compare central sensitization in the
interictal vs. migraine attack state in a within-subject design.
Temperatures were delivered using a 1?661?6 cm contact
thermode (TSA-II, medoc Advanced Medical Systems, Ramat
Yishai, Israel). Only the side of the face that was reported as
sensitive during migraines by the patients was tested. The hand
(dorsum) tested was on the same side as that for the face. The
controls were matched to their corresponding migraine patient
with regard to the side of the face tested.
Heat pain thresholds were determined using an ascending
method of limits. Subjects were presented with a 32uC baseline
temperature that increased 1uC/sec until they indicated their first
detection of pain. Pain threshold was calculated as the average of
Functional scans began with 40 sec of the baseline temperature
(32uC) followed by three 15 sec stimuli, each separated by 30 sec.
The rate of temperature change was 4uC/sec.
MRI scanning and image analysis
Imaging was conducted using a 3T Siemens Trio scanner with a
quadrature head coil. Anatomical images were acquired with
established imaging parameters . For functional scans, a
Gradient Echo (GE) echo planar imaging (EPI) sequence with
TE/TR=30/2500 was performed, with seventy-four volumes
acquired. Each functional scan consisted of 33 slices oriented in an
oblique plane to match the brainstem axis. This orientation of
acquisition has proven useful for the functional imaging of
brainstem structures [17–19]. Slices were 3?5 mm thick with in-
plane resolution of 3?5 mm (64664).
Functional imaging datasets were processed and analyzed using
scripts within FSL 4?0 (FMRIB’s Software Library, www.fmrib.ox.
ac.uk/fsl) . Image preprocessing was performed as previously
described , with the exception that 5 mm FWHM spatial
smoothing was used during preprocessing. First-level fMRI analysis
of single subject data was performed using FMRI Expert Analysis
Tool using FMRIB’s Improved Linear Model (FEAT FILM)
Version 5?4 with local autocorrelation correction . Individual
subjects were co-registered with respect to their brainstem for
mixed-effectcontrast group analysisofmigraine vs. healthysubjects,
and contrast maps were thresholded at z=1?6 without correction
formultiplecomparisons.Single trial averages werecalculatedusing
in-house programs incombination with functional time courses
and an anatomically defined region of interest for NCF.
Other brainstem regions also involved in pain modulation
(parabrachial nucleus and PAG) are located in close proximity to
the NCF. However, we do not believe our activations involve the
medial or lateral parabrachial nuclei for the following reasons: (1)
our activation contrasts are in a similar location to those observed
in other functional studies of healthy volunteers [14–16]; and (2)
the parabrachial nuclei are located inferior to the NCF. We only
observed dorsolateral PAG changes in one stimulus condition.
For the 41uC stimulus, the area of the dorsolateral pons
centered on the NCF showed significantly greater activation in
control subjects than the migraine patients (Fig. 1). This area of the
brainstem, albeit with less spatial resolution, has previously been
found active during migraine attacks in positron emission
tomography studies [3,5]. Activation in NCF was observed
bilaterally for the face stimulation site, and was predominantly
contralateral for the hand (Table 1). In both cases, inspection of
the group activation map for healthy subjects revealed significant
activation in this area, whereas migraine patients did not show
significant activation. In addition, trial averages that relate to the
timing of the stimuli show distinguishable temporal responses in
the healthy controls (Fig. 1). Pain intensity ratings (0=no pain;
10=max pain) to the 41uC stimulus were not significantly
different between the migraine and control groups (Fig. 1).
The noxious heat stimulus (Thr+1uC) applied to the face and
hand resulted in significant activation of this same NCF region in
both migraine and control subjects. At this higher intensity level,
the NCF activation in the control subjects was significantly greater
than in migraine subjects for stimuli applied to the hand, though
not the face (Fig. 1; Table 1). The average temperature applied
was 4763uC, and was not significantly different for the migraine
and control groups, and neither for the face and hand (2-Way
repeated measures ANOVA [group, site], group F=0?7814,
p=0?3872, df=1, site F=0?1677, p=0?6865, df=1). Pain
intensity ratings were not significantly different between the
groups or stimulation sites (Fig. 1).
The decreased relative activation in NCF of the migraine group
suggests a dysfunction in this brainstem descending pain
modulatory system. NCF sends dense neural projections to the
rostroventral medulla , which directly modulates dorsal horn
nociceptive transmission neurons in the spinal cord and in the
analogous medullary dorsal horn [6,24]. NCF receives reciprocal
input from lamina I dorsal horn neurons [25–27], which may
drive its activation and thus complete a possible negative-feedback
loop . Inputs to the NCF from higher brain structures related
to modulatory processing may also contribute to NCF output
Migraine Brainstem Dysfunction
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[6,15,28]. In the healthy group, the NCF activation we observed
with both 41uC and noxious heat could be conceivably driven by
thermal and nociceptive inputs from lamina I in the trigeminal
nucleus (face)/dorsal horn (hand) , as well as wide dynamic
range neurons in deeper lamina such as IV and V .
In addition to the aforementioned structural connectivity data,
functional investigations of NCF are suggestive of a role in
descending pain modulation. Animal and human studies have
suggested that the NCF can inhibit and facilitate nociception
through cholinergic and glutamatergic mechanisms, which may be
triggered by noxious stimulation, central sensitization, as well as
the expectation of pain. In animal studies, electrical stimulation of
NCF produces opioid-mediated analgesia through excitatory
cholinergic projections to the nucleus raphe magnus (NRM)
Figure 1. Functional differences in the brainstem and the brain of migraine vs. healthy control subjects. (A) Pain ratings: No significant
effects of group or stimulation site for 41uC (2-Way repeated measures ANOVA [group, site], group F=0?3646, p=0?5521, df=1, site F=2?7355,
p=0?1123, df=1) and Thr+1uC (2-Way repeated measures ANOVA [group, site], group F=0?2918, p=0?5950, df=1, site F=0?4060, p=0?5312, df=1).
Mig=migraine subject; HC=healthy control. (B) Activation contrast: Interictal migraine subjects show decreased nucleus cuneiformis (NCF)
responses to stimuli relative to controls. The exception is Thr+1uC on the face. The green area in the reference images highlight NCF (adapted from
Duvernoy). C=contralateral to stimulus site; I=ipsilateral. p,0?05 (uncorrected). (C) Single trial averages: Responses recorded from anatomically
defined NCF region of interest. Y-axis=normalized % signal change. Gray shade represents stimulus application. N=12 in each condition, except for
Thr+1uC for Face (N=11). One patient was excluded because of stimulus-correlated motion; the corresponding control was also excluded.
Table 1. Summary of group activation contrasts of interictal migraine vs. control within the NCF.
StimulusSiteSide Peak z-statisticPeak z-stat MNI152 x,y,z Volume (mm3)
22.9 10,228,222 160
22.7 10,228,222 104
C=Contralateral to affected side.
I=Ipsilateral to affected side.
NCF ROI volume=648 mm3.
Migraine Brainstem Dysfunction
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[9,11]. Additionally, electrical stimulation or microinjection of
morphine into NCF in the rat can also activate glutamatergic
projections to the NRM, leading to modulation of pain-related
behaviors [10,13]. In addition to the NCF-NRM pathway, recent
evidence suggests that morphine microinjection into NCF may
activate a compensatory descending modulatory pathway when
the NRM is lesioned . Human imaging studies have reported
that activations in NCF and the rostroventral medulla are
correlated during repeated noxious stimulation , and also that
NCF may activate during punctate mechanical hyperalgesia,
suggesting that it is involved in a alterations in descending pain
modulation . NCF is also activated during the expectation of
pain, indicating that awareness of impending pain can trigger a
preparatory modulatory process in NCF .
We interpret our results as follows: NCF hypofunction is a
characteristic of migraine sufferers that is detectable during their
interictal phase, and reflects a dysfunction of descending
modulation. The dysfunction we observed may be a result of
damage secondary to a history of repeated migraine attacks [30–
32]. However, the mechanism of such damage is not known
although a neurovascular etiology has been suggested. Though the
hypofunction we observed intuitively suggests a decrease in
inhibition, the NCF is an integrative structure that contains both
‘off’ and ‘on’ cells , and a decrease in the overall level of
activation would not rule out the presence of enhanced facilitation.
The hyperexcitability of nociceptive circuitry downstream of the
NCF may contribute to central sensitization at the onset of
migraine. NCF dysfunction could thus lead to progressive changes
in the spinal trigeminal nucleus (localized allodynia), and/or the
thalamus and spinal cord (generalized allodynia). However, note
that while NCF hypofunction was found in migraineurs during
their interictal phase, the NCF dysfunction may change or even be
supplanted by abnormalities in other brain regions during the
different phases of an actual migraine attack.
The absence of a difference between migraine and control
subject NCF activation for noxious stimuli to the face in migraine
patients (Fig. 1) is unexpected, in light of the impaired descending
modulation model. We speculate that the NCF dysfunction
manifests only when insufficient afferent drive is present to fully
trigger the descending modulatory system. In other words,
increased afferent drive may be required to overcome the NCF
dysfunction to activate descending inhibition. In migraine patients,
noxious heat applied to the face may more effectively activate
descending modulatory circuitry relative to the control group,
whereas non-noxious heat did not seem to activate descending
inhibition to the same extent. That this speculative intensity-
dependent relationship appears to be specific to the face could be
attributed to the involvement of potentially sensitized trigeminal
afferents in migraine patients. At higher intensity levels than used
in this study, increased afferent drive may also recruit activation of
other modulatory centers (e.g., PAG). The existence of such an
intensity-dependent activation of the descending modulatory
system is mere conjecture at this point.
Why would a non-noxious stimulus (41uC) activate a brainstem
modulatory region like the NCF? Several possible explanations
may account for this: (1) 41uC is known to activate nociceptors,
and what we observe may reflect an enhancement of their
sensitivity; (2) since NCF sends descending projections to second-
order wide dynamic range neurons , which encode both non-
noxious and noxious stimulus intensities, perhaps NCF also affects
innocuous stimulus processing at sub-perceptual levels in the
migraine interictal phase; (3) low-threshold C-fiber afferents may
convey other information that differentially activate or involve
descending modulatory systems , including the NCF; (4)
corticobulbar input in migraine patients may differentially
modulate NCF activity  regardless of stimulus intensity via a
sensory-cognitive mechanism; (5) the interictal migraine brain may
be hyper-excitable in regards to general sensory processing ,
which may or may not include the involvement of NCF. These
explanations expand the possible role of descending modulatory
processing in migraine.
How is it possible to see differences in modulatory circuitry
without seeing a difference in pain sensitivity between migraine and
healthy subjects using comparable stimuli? While we do not know
the specific answer to this question, there are a number of possible
explanations. NCF can be triggered during the anticipation of pain,
before a stimulus is even applied [15,37]: this suggests that the
perception of physical stimuli is not necessary for NCF activation,
and that cognitive processes may influence NCF activation in
healthy subjects perhaps more effectively than in migraine patients.
In addition, structural changes detected in this region of the
brainstem [1,2,38], which includes white matter changes, may alter
the coupling of the blood-oxygen-level- dependent response and
neural activity . The latter interpretation leaves open the
possibility that NCF in interictal migraine patients may function
perfectly well, but that the fMRI signal itself is dissociated with
neural activity in this area. Finally, patient medications may have
dampened the fMRI signal, given that healthy controls were free of
medications. However, this possibility is perhaps less likely given
that: (1) eight out of twelve patients were not taking pre-emptive
medications for their migraine, (2) patients discontinued their
medications for one dosage cycle prior to imaging, (3) the significant
changes observed were specifically localized to NCF, and were not
global as might be expected for a drug, and (4) the heterogeneity of
the medications taken by the patients reduces the likelihood of a
mass action of any one pharmacological mechanism influencing the
fMRIsignal.An important caveat is that intermittentuseofabortive
migraine medications may have unknown long term effects on
We expected to observe changes in the PAG given its
involvement in descending modulation during migraine attacks
. The relationship between the NCF and PAG in descending
modulation is incompletely understood, but they share cytoarchi-
tectural homology  and are extensively connected [35,40].
However, only in one condition (Hand Thr+1uC) did we observe
hypofunction in the dorsolateral PAG (data not shown). We
interpret this negative result as an indication that PAG may only
be recruited in descending modulation with higher levels of pain,
such as that experienced during migraine.
We propose that NCF hypofunction in migraine patients
contributes to central sensitization during attacks through partial
loss of inhibition and/or enhanced facilitation of ascending
nociceptive pathways. A prevailing theory to explain the
occurrence of migraine attacks is that hyperexcitability develops
along the trigeminovascular pathway . Disruption of a
descending modulatory system in migraine patients could cause
such hyperexcitability, and has been previously hypothesized to be
an underlying cause for migraine pathology [5,41–43]. While this
state of putative disinhibition/facilitation did not appear to impact
the perception of thermal stimuli during the interictal phase, we
hypothesize that it may facilitate central sensitization at the onset
of migraine. In our migraine patients, we found that NCF
activation was disrupted not only for stimuli applied to the face,
but also the hand. This relationship suggests that for migraineurs
with extended allodynia, the disinhibition/facilitation of the
encoding of noxious heat that accompanies NCF dysfunction is
not specific to the head, but may be generalized to other parts of
Migraine Brainstem Dysfunction
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Currently, drugs that are developed to treat migraine have
focused on alleviating symptoms during a migraine attack.
However, migraine patients have shown abnormalities in cortical
sensory processing even between migraine attacks. Using innoc-
uous and noxious thermal stimuli as test stimuli, we have identified
specific brain structures that are hypofunctional in migraine
patients when they are not having an attack. This model may be a
useful surrogate in evaluating pre-emptive or disease modifying
therapies for migraine patients. Considering that recurrent
episodic migraines appear to transform into severe daily headache
, this brainstem dysfunction could be used to evaluate
treatments to prevent this transformation . Future studies
should evaluate the potential of current and future migraine
preventative agents to correct this dysfunction, thereby improving
descending inhibition and reducing headache frequency.
Found at: doi:10.1371/journal.pone.0003799.s001 (0.06 MB
Conceived and designed the experiments: RB LB DB. Performed the
experiments: EAM RB SET DB. Analyzed the data: EAM SET.
Contributed reagents/materials/analysis tools: RB RH LB. Wrote the
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PLoS ONE | www.plosone.org5 November 2008 | Volume 3 | Issue 11 | e3799