A JOURNAL OF NEUROLOGY
Morphing voxels: the hype around structural
imaging of headache patients
Department of Systems Neuroscience, University of Hamburg, Hamburg, Germany
Correspondence to: Arne May, MD,
Department of Systems Neuroscience,
Universita ¨ts-Krankenhaus Eppendorf (UKE),
Martinistr. 52, D-20246 Hamburg,
Neuroimaging analysis using structural data has begun to provide insights into the pathophysiology of headache syndromes.
Several independent studies have suggested a decrease in grey matter in pain-transmitting areas in migraine patients. Most of
these data are discussed as damage or loss of brain grey matter, reinforcing the idea of migraine as a progressive disease.
However, given what we know about the nature of morphometric changes detectable by the methods we have to date, this
interpretation is highly speculative and not supported by the data. It is likely that these changes are the consequence and not
the cause of the respective headache syndromes, as they are probably not irreversible and only mirror the proportion or duration
of pain suffered. Moreover, structural changes are not headache specific and have to be seen in the light of a wealth of pain
studies using these methods. The studies in cluster headache patients prompted the use of stereotactic stimulation of the
hypothalamic target point identified by functional and structural neuroimaging. Due to the nature of the methods used and due
to a high anatomical variance it is more than questionable to use this point as a definite answer to the source of the headache in
clusters and even more so when it is uncritically used in individuals. We need a way to study each patient individually using the
functional imaging method with the highest spatial and temporal resolution available to enable us to target the seed point
for deep brain stimulation on this individual basis. One of the major future challenges is to understand the behavioural
consequences and cellular mechanisms underlying neuroanatomic changes in pain and headache.
Keywords: headache; migraine; morphometry; brain; VBM; functional imaging
Traditionally, studies of brain morphology completely depended
on autopsy material. This situation changed with the advent
of modern in vivo imaging methods, in particular magnetic reso-
nance (MR) imaging. While early imaging studies of the brain
provided a qualitative description of normal brain morphology
and its deviations in disease states, more recently developed
MR-based methods allow a quantitative evaluation of brain mor-
phology (Draganski and May, 2008). The whole assortment of
these MR-based methods comes under the heading of MR
morphometry of the brain. One of the immense advantages is
the in vivo observation of temporal changes in brain morphology
and the correlation of brain morphology with brain function
(Ashburner et al., 2003). Normally, three-dimensional, high-
resolution, T1-weighted MRI images acquired with conventional
1.5T MR scanners and 1mm3voxels provide sufficient detail
and contrast. One of the widely spread and validated morpho-
metric techniques used to capture structural alterations in the
brain is voxel-based morphometry (VBM). VBM is a whole brain
method for analysis of automatically pre-processed structural
high-resolution MRI data treating images as continuous scalar
doi:10.1093/brain/awp116 Brain 2009: 132; 1419–1425 |
Received February 5, 2009. Revised April 2, 2009. Accepted April 7, 2009
? The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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measurements (Draganski and May, 2008). VBM is relatively
simple to use, has moderate demands on computational resources
and is available in common software packages like FSL or SPM.
This technique relies on the segmentation of MR images into
different tissue types (grey matter, white matter and CSF) using
information derived from image intensity. The grey matter map, as
a result of this segmentation, thus describes the spatial distribution
for each individual at the level of every voxel. Additional a priori
knowledge about the spatial distribution of different tissue types
can be applied to refine this segmentation process. To take advan-
tage of this approach, MR data have to be registered to the same
stereotactic space as the a priori images—making the segmen-
tation accuracy sensitive to registration errors. Because of this
dependency of registration errors, several approaches have been
developed to improve registration accuracy, such as the use of
segmented images for registration rather than MR images (Good
et al., 2001b), a combined model of image registration, tissue
classification and bias correction (Ashburner and Friston, 2005),
or the application of high-resolution registration methods (Shen
and Davatzikos, 2003). These solutions have been implemented
in advanced VBM protocols, which then allow voxel-wise statisti-
cal testing of grey matter volume in each voxel.
Morphometric studies in
The pioneering study using VBM to find possible brain differences
between headache patients and healthy volunteers found a
significant structural difference in grey matter density, a ‘lesion’
coinciding with the inferior posterior hypothalamus, in cluster
headache (May et al., 1999), which showed a co-localization of
morphometric alterations and functional activation in cluster head-
ache patients (May et al., 1999). These studies prompted the use
of stereotactic stimulation (DBS) of this target point identified by
functional and structural neuroimaging (May, 2008b). Until now,
headache patients have been reported (Leone et al., 2008).
However, the method of hypothalamic DBS is not without risk
(Schoenen et al., 2005) and it does only work in about 50% of
patients (Bartsch et al., 2008; Leone et al., 2008). One of the
reasons why it only works in some patients and not in others
could be the fact that the target point is not exactly defined in
patients where higher voltage is needed and is simply wrong in
those patients where hypothalamic DBS does not work. This target
point was taken directly from the structural and functional studies
mentioned above. It needs to be pointed out that these studies are
the result of group studies and that the original data needed to
be normalized into a stereotactic space and additionally, are
smoothed with a filter kernel of at least 10mm. It is more than
questionable to use this point as a definite answer to the source of
the headache in cluster and even more so when it is uncritically
used in individuals. The anatomy is different (the simple reason
why normalization is used in functional neuroimaging) and these
subtle differences are corrected in the normalization process
(Ashburner and Friston, 1999, 2000). Although the original work
by Franzini and Leone (Leone et al., 2001) is ingenious in that it is
the first and only time that functional imaging was directly trans-
lated into a treatment, which in turn proved to be effective.
This work definitely opened new avenues in cluster headache
treatment. However, the more we learned about this method
over the last 8 years, the more we have to ask ourselves whether
the discussion about the target region should be exhausted by
discussing the correct name (e.g. hypothalamic grey versus ventral
tegmentum, etc.) of this anatomical point which is undoubtedly
syndromes (May, 2005). We need more and better studies and,
above all, we need to address the question of individual anatomy
and possible anomalies. We need a way to study each patient
individually using the functional imaging method with the highest
spatial and temporal resolution available to enable us to target the
seed point for deep brain stimulation on this individual basis.
Chronic tension type headache
Recently, 20 patients with chronic tension type headache (CTTH)
were compared to healthy volunteers and showed a significant
decrease in grey matter in the dorsal rostral and ventral pons,
the perigenual cingulate cortex, the middle cingulate cortex and
the right posterior cingulate cortex, the anterior and posterior
insulae bilaterally, the right posterior temporal lobe, the orbito-
frontal cortex and parahippocampus bilaterally and the right
cerebellum. Interestingly, this decrease in grey matter correlated
positively with increasing headache duration in years, i.e. patients
with longer history had less grey matter in these regions (Schmidt-
Wilcke et al., 2005). In the same paper, patients with medication
overuse showed a non-significant decrease in the left orbito-
frontal cortex and the right midbrain. As the change in grey
matter in chronic tension type headache patients was restricted
to structures involved in pain processing, the authors concluded
that these data may be interpreted as the consequence of central
sensitization, generated by prolonged nociceptive input from the
pericranial myofascial tissues (Schmidt-Wilcke et al., 2005).
Regarding migraine, a pioneering study by Matharu et al. did not
find any significant morphometric changes in grey or white matter
in patients suffering from episodic migraine (Matharu et al.,
2003). However, five more recent studies question this negative
finding. The first one was published by Rocca et al. who investi-
gated 16 migraine patients with T2-visible abnormalities and
15 matched controls using VBM and reported an increased density
of the PAG and of the dorsolateral pons in migraine patients
(Rocca et al., 2006). The authors also found a decrease in grey
matter in the anterior cingulate cortex (ACC) and both insulae in
migraine patients. One possibility why this study found structural
changes in migraine, whereas an earlier study did not, may be the
fact that the study by Rocca et al. used a scanner with higher
field strength (3T) whereas the former studies were done on a
1.5T scanner. However, the migraine cohort was rather small
Brain 2009: 132; 1419–1425A. May
(16 patients) and comprised of patients with T2-visible brain
lesions, a finding which is not part of the IHS criteria (Headache
Classification Committee of the International Headache Society,
2004). Population-based findings suggest that some patients
with migraine (with and without aura) are at an increased risk
for sub-clinical lesions in certain brain areas (Kruit et al., 2004;
Tietjen, 2004), which was also suggested by a meta-analysis
(Swartz and Kern, 2004). Although it is more than questionable
that these white matter changes are true vascular infarcts, given
that they can vanish spontaneously (Rozen, 2007; Agarwal et al.,
2008), it has been shown that they are independent of right-to-
left shunts (Adami et al., 2008) and therefore cannot simply be
attributed to the occurrence of a patent foramen ovale (PFO)
(Dowson et al., 2008), as has been discussed before (Wilmshurst
et al., 2000, 2006). In any case, studying only migraine patients
with visible MR-lesions may imply a significant bias. Nevertheless,
the findings of this study were, in essence, replicated by four other
independent studies so far (Kim et al., 2008; Schmidt-Wilcke
et al., 2008; Schmitz et al., 2008; Valfre et al., 2008). All of
these studies reported a decrease in grey matter in the frontal
and temporal cortex. The first one was published by Valfre et
al., who investigated 27 migraine patients and 27 healthy controls
(Valfre et al., 2008). In comparison with controls, migraineurs
presented a significant focal grey matter reduction in the right
superior temporal gyrus, right inferior frontal gyrus and left
precentral gyrus. Dividing the patients into episodic and chronic
migraine (n=11), chronic migraine patients showed a focal grey
matter decrease in the bilateral anterior cingulate cortex. Other
clusters were found in the amygdala, the parietal operculum, the
frontal gyrus and bilateral insula. Comparing all the migraine
patients with controls, a significant correlation between grey
matter reduction in the anterior cingulate cortex and the
frequency of migraine attacks was found (Valfre et al., 2008).
The authors concluded that this study supports the concept that
migraine is a progressive disorder (Valfre et al., 2008). The same
conclusion was drawn by another study investigating 28 patients
and demonstrating less grey matter in the frontal lobes, brainstem
and the cerebellum in migraineurs. In this study, both the attack
frequency and the disease duration correlated with the extent of
grey matter reduction and the authors interpreted this finding as
an indicator for ‘brain damage’ in migraine. The third study was
published by Kim et al. who compared grey matter volume
between 20 migraine patients (5 with and 15 without aura)
with 33 healthy controls matched for age and sex (Kim et al.,
2008). Although the statistics have to be seen with caution,
given the different sample size per cohort, the findings are
remarkably similar to the ones above: migraine patients had signif-
icant grey matter reductions in the bilateral insula, motor/premo-
tor, prefrontal, cingulate cortex, right posterior parietal cortex and
orbitofrontal cortex (Fig. 1). Moreover, all of these regions were
negatively correlated with headache duration and lifetime head-
ache frequency. The authors interpret their findings—they ‘sug-
gest that repeated migraine attacks over time result in selective
damage to severalbrain regions
The biggest study so far was published by Schmidt-Wilcke et al.
who compared 35 patients suffering from migraine with 31 healthy
involved in centralpain
controls with no headache history. They found a decrease in grey
matter in the anterior and middle cingulate cortex in migraineurs
(Schmidt-Wilcke et al., 2008). The authors discussed their findings
in context with recent findings in chronic pain states, such as
chronic phantom pain (Draganski et al., 2006b) and chronic
back pain (Apkarian et al., 2004) and suggested that the grey
matter change in migraine patients is the consequence of frequent
nociceptive input and should thus be reversible when migraine
attacks cease (Schmidt-Wilcke et al., 2008). In summary, all but
the last study in migraine interpreted their finding—a focal reduc-
tion in grey matter—as a damage of the brain or as an indicator
that migraine is a progressive disease. This argumentation dis-
regards the point that migraine is a self-remitting disease which
usually resolves with age. Until longitudinal studies, which assess
whether these changes also recede, have been conducted,
we should not over-interpret these data as ‘brain damage’. In this
context it is interesting that chronic tension type headache does not
always resolve with age and that morphometric changes seen in
these patients may theoretically be more functionally relevant.
Morphometric changes in
Any morphometric findings in headache patients have to be seen
in the light of a wealth of morphometric studies in chronic pain
Figure 1 Summary of the structural (voxel-based
morphometry) data of all studies cited in the text. For each
paper all available stereotactic coordinates were included in a
meta-analysis (http://www.brainmap.org/index.html) using
GingerALE via the activation likelihood estimation (ALE)
method. We used a 10 mm full-width at half maximum filter
and 5000 permutations to determine the null distribution of the
ALE statistic at each voxel. We used a normalized template as
the anatomical underlay and the thresholded ALE results as
the overlay. The colours code the different headache types
investigated so far and show the finding for each headache
type in Talairach space. Papers showing significant activations
which form the results of this analysis are cited in the text. Red:
migraine; blue: cluster headache; yellow: tension type
VBM in headacheBrain 2009: 132; 1419–1425 |
(May, 2008a) and exercise-dependant plasticity (Duerden and
Laverdure-Dupont, 2008). In the last 2 or 3 years, several studies
have been published, which demonstrated structural brain changes
in chronic pain syndromes. A striking feature of all of these studies
is the fact that the grey matter changes were not randomly
distributed but concerned defined and functionally highly specific
brain areas—namely, involvement in supraspinal nociceptive
processing. The most prominent findings were different for each
pain syndrome, but overlapped in the cingulate cortex, the orbito-
frontal cortex, the insula and dorsal pons (May, 2008a). Further
structures comprise the thalamus, basal ganglia and parahippo-
campus bilaterally. All of the studies conducted so far in chronic
pain syndromes, including fibromylagia (Kuchinad et al., 2007),
irritable bowel syndrome (Davis et al., 2008), phantom pain
(Draganski et al., 2006b), chronic back pain (Apkarian et al.,
2004; Schmidt-Wilcke et al., 2006) and thoracic spinal cord
injury (Wrigley et al., 2008) showed a decrease in some of the
above-mentioned areas. Nevertheless, all available clinical MR
morphometric studies have their limitations. One of the major
drawbacks is the poor comparability of studies from different
research centres. In addition, many studies were done in small
patient samples and did not analyse the temporal dynamics and
the determinants of brain morphological changes. Consequently,
routine clinical application of MR-based morphometry is currently
not feasible. However, the fact that the above mentioned findings
in migraine and tension type headache have been replicated by
nearly all studies investigating brain changes in patients suffering
from all sorts of chronic pain, suggest that these findings are not
specific to head pain but to the chronicity of pain. If it is true that
chronic pain patients have a common ‘brain signature’ in areas
known to be involved in pain control, the question arises whether
the central reorganization processes in chronic pain syndromes
could involve a ‘degeneration’ of specific brain areas. This question
is not redundant as a degenerative process is irreversible. Although
some of these studies in chronic pain also fall for the assumption
that a decrease in brain grey matter must mean a damage to the
brain (Apkarian et al., 2004; Kuchinad et al., 2007), the crucial
question is what do we measure when we measure grey matter?
The neurobiological basis of structural alterations (increase or
decrease in grey matter demonstrated by VBM) on a microscopic
level are not well defined. VBM detects changes in grey matter
concentration per voxel as well as changes in the classification of
individual voxels, e.g. from white to grey matter (Good et al.,
2001a) and probably a combination of both. In general, a
decrease in grey matter could be due to a simple decrease in
cell size, atrophy of neurons or glia, inactivation of spine density
or even changes in blood flow or interstitial fluid. Unfortunately,
all available studies compared cohorts of patients and therefore no
statement regarding dynamic changes can be made. In some
respects, this situation resembles that in the functional MRI-field
some years ago, when its use for our understanding of brain func-
tion was not debated, yet the long-supposed physiological corre-
late of the BOLD-signal was not yet proven (Logothetis and
Pfeuffer, 2004). As long as the causes of these changes on a
histological–anatomical level remain unresolved, the clinical rele-
vance of MR morphometric results is limited.
In vivo demonstrations of a change in brain structure could
represent a neuroanatomical substrate for the respective disease
(Reiss et al., 2004) or just an epiphenomenon or even an artefact.
In this respect, any data that demonstrate a population difference
between patients and controls must be regarded with caution as
long it is not known whether such changes are the cause or the
consequence of the disease (Weiller and Rijntjes, 1999). It is
unquestionable that changes in the periphery, i.e. loss of afferent
input due to unilateral amputation of an extremity, may change
the brain structure of individuals (Draganski et al., 2006a). Recent
studies also suggested that abnormalities in the cerebral cortex of
subjects with amblyopia (Mendola et al., 2005), strabismus (Chan
et al., 2004) and even amaurosis (Noppeney et al., 2005) exist,
possibly as a result of experience-dependent neuronal plasticity
(Draganski and May, 2008). As a non-invasive procedure, MR
morphometry is the ideal tool for the quest to find the morpho-
logical substrates of diseases, deepening our understanding of the
relationship between brain structure and function and even to
monitor therapeutic interventions. One of the great challenges in
the future is the validation of morphometric methods as well as
the development of a reliable means that allows the pooling of
data from several scanners and centres. With the application of
these methods, MR-based morphometry will become an extremely
powerful tool for multi-centre and therapeutic trials of several
The brain in pain: dynamic
alterations and neuronal
Considering that activation-dependant brain plasticity in humans
on a structural level has already been demonstrated in adults
(Draganski et al., 2004; Boyke et al., 2008), it is an interesting
question whether repeated painful stimulation may lead to struc-
tural changes of the brain. In a very recent study, 14 healthy
subjects were stimulated daily with a 20-min pain paradigm for
8 consecutive days, using structural MRI performed on Days 1, 8,
22 and again after 1 year. Using voxel-based morphometry,
it was demonstrated that repeated painful stimulation resulted
in a substantial increase of grey matter in classical somatosensory
areas, including the mid-cingulate and somatosensory cortex
(Teutsch et al., 2008). These data are in line with most morpho-
metric studies investigating structural brain plasticity as a result of
exercise and learning (Gaser and Schlaug, 2003; Draganski et al.,
2004; May et al., 2007). The changes in brain structure are usually
exclusively demonstrated in brain areas which are ascribable to the
task, just as in the present study, where changes are only seen in
somatosensory areas. Moreover, the finding of structural changes
follows the previously described functional pattern (Bingel et al.,
2007) precisely, i.e. a significant change during the protocol which
reverses to pre-stimulation levels at the fourth time-point, i.e. after
1 year. It is an intriguing fact that chronic pain patients suffer
constant pain, but seem not to develop an increase in grey
matter in somatosensory areas, although several studies showed
that exercise is accompanied by an increase of grey matter in the
Brain 2009: 132; 1419–1425 A. May
regions which are specific for the respective task (for review see
May and Gaser, 2006). One explanation for this lack of grey
matter increase in chronic pain patients is that they do not have
a significant noxious input (any more). In that case, the experience
of constant pain is mostly driven by the brain itself and the
afferent (peripheral noxious) input is no longer needed for this
experience. Another possibility is that a given task-specific exercise
will only increase grey matter in corresponding brain areas until
the task is learned and that this change recedes once the task is
It is not understood why only a relatively small proportion of
humans develop a chronic pain syndrome, considering that pain is
a universal experience. The question arises whether in some
humans a structural difference in central pain transmitting systems
may act as a diathesis for chronic pain. In the course of chronicity,
numerous modulatory mechanisms have been postulated and
altogether addressed as ‘neuronal plasticity’ (Woolf and Salter,
2000) and structural changes of the brain may be added to this
list (May, 2008a). There is no conclusive data regarding the cause
or the consequence of the different cortical and subcortical
morphological changes that have been observed in chronic pain
states, although the correlation of pain duration and the degree of
grey matter decrease in most studies suggests that the morpho-
logical changes are, at least in part, secondary to constant pain.
Which structural changes are
specific for headache?
Given that nearly all studies investigating structural changes in
different headache syndromes found similar results and given
that these results have been found in most studies of chronic
pain as well, one has to address these changes, namely a decrease
of grey matter in pain transmitting structures, as non-specific for a
given headache or pain syndrome and further studies will be
required to definitively address this issue. As most changes corre-
late to pain duration, it seems plausible to argue that the alteration
of this region is a consequence, rather than a cause, of frequent
nociceptive input. The nature of chronic pain makes it difficult to
prove this point. Regarding headache, however, it is not known
why migraine usually remits with age. It is a very interesting
question for future studies whether the morphological changes
reverse when migraine, and hence the disproportionate amount
of nociceptive stimulation, stops.
Two studies reported structural changes which may be specific
for the respective disease: the hypothalamus in cluster headache
(May et al., 1999) and the brainstem in migraine (Rocca et al.,
2006). The data on cluster headaches describe an increase in grey
matter which follows the functional pattern during the acute
headache attack (May et al., 1998). The study in migraine patients
reported an increased density of grey matter in the dorsal pontine
region, at virtually the same location as the activation reported in
the migraine PET studies. The anatomical co-localization of
functional and structural changes raises the possibility that the
observed changes may be causal rather than a consequence of
the pain. In both cases the question arises whether these changes
(an increase of regional grey matter rather than a decrease) reflect
the above mentioned morphometric studies investigating structural
brain plasticity as a result of exercise and learning. Further studies
need to be done and as migraine has a strong genetic component,
the ideal inclusion criteria for future studies to render groups as
homogenous as possible could be based on genotype (cohort
study) or response to treatment (longitudinal study including
controls). However, any data of a decrease in grey matter in head-
ache syndromes need to be seen in the light of all the intelligence
which has been gathered in the last 10 years and probably do not
justify the discussion of brain damage or whether or not the dis-
ease is progressive.
Limitations of VBM
As a non-invasive procedure, MR Morphometry has the potential
to be the ideal tool for the quest to find the morphological
substrates of diseases, deepening our understanding of the rela-
tionship between brain structure and function and even to monitor
therapeutic interventions. VBM is for research purposes only and
requires groups of at least 20 subjects per group to produce stable
results (May and Gaser, 2006). However, headache and pain
studies thus far suffer relatively often from small sample sizes
and selected patient samples (e.g. cases from specialized centres
rather than population cases). Given that the groups which are to
be compared need to be highly homogenous, an excellent and
However, who is the proper control for a migraine study: volun-
teers who claim to never have experienced a headache in their life
or volunteers who just have no migraine and no first-grade family
member with migraine? Both choices make this very challenging
due to recall issues, and the long-term nature of the disorder.
Perhaps structural studies of a condition that is potentially
genetically heterogenous, such as migraine, miss subtle changes
that might segregate with a more homogenous genotype
(Matharu et al., 2003). The advantage of VBM is that it is fully
automated and allows for changes elsewhere in the brain
and thus avoids observer bias, and moreover, it incorporates a
imaging modalities/equipment/analysis and, above all, image
pre-processing steps such as smoothing, registration, choice of
small volume correction, etc. may well account for differences in
VBM-findings. Until there is a better standardization between
and Gaser, 2006) we need to be cautious not to overinterpret
morphometric data in headache patients.
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VBM in headache Brain 2009: 132; 1419–1425 |