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Chronic pain may change the structure of the

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Article in Pain August 2008
DOI: 10.1016/j.pain.2008.02.034 Source: PubMed

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Pain 137 (2008) 715

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Review

Chronic pain may change the structure of the brain

Arne May *
Department of Systems Neuroscience, University of Hamburg Eppendorf (UKE), Martinistrasse 52, D-20246 Hamburg, Germany
Received 30 November 2007; received in revised form 21 February 2008; accepted 27 February 2008

Abstract
Recently, local morphologic alterations of the brain in areas ascribable to the transmission of pain were detected in patients suffering from phantom pain, chronic back pain, irritable bowl syndrome, bromyalgia and two types of frequent headaches. These
alterations were dierent for each pain syndrome, but overlapped in the cingulate cortex, the orbitofrontal cortex, the insula and
dorsal pons. These regions function as multi-integrative structures during the experience and the anticipation of pain. As it seems
that chronic pain patients have a common brain signature in areas known to be involved in pain regulation, the question arises
whether these changes are the cause or the consequence of chronic pain. The author suggests that the gray matter change observed in
chronic pain patients are the consequence of frequent nociceptive input and should thus be reversible when pain is adequately
treated.
2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keywords: Brainstem; Chronic pain; Chronication; Cingulate cortex; Imaging; Neuroplasticity; Voxel-based morphometry (VBM)

1. Introduction
In the past decade of pain research, a network of
pain-transmitting areas within the CNS has been established, based on both animal studies [75] and ndings
from functional imaging studies in humans [58]. Consequently, the neurobiology of pain is increasingly understood as an integration of activity in distinct neuronal
structures. Evidence of altered local brain chemistry
and functional reorganization in chronic back pain
patients supports the idea that chronic pain could be
understood not only as an altered functional state, but
also as a consequence of central plasticity [20]. Recent
neurobiological ndings suggest cortical reorganization
on a functional level [33]. For example, amputation of
a limb is very often accompanied by phantom pain. In
these patients, the deaerentation leads to cortical reorganization where the representational elds of adjacent
*

Tel.: +49 (0) 40 42803 9189; fax: +49 (0) 40 42803 9955.
E-mail address: a.may@uke.uni-hamburg.de

areas move into the representation zone of the deaerented limb [25,61]. This functional reorganization
was not only detected in patients suering from phantom limb pain [23], but also in chronic back pain
patients [21]. Regarding chronic back pain, increased
cortical activity and a shift of the cortical representation
of the back, which was interpreted as an expansion of
the backs representation into the neighboring foot
and leg area [21], was found. In patients suering from
chronic regional pain syndrome (CRPS Typ I), a shrinkage of the representational eld of the aected arm was
found and the extent of shrinkage correlated highly with
the intensity of pain and the magnitude of mechanical
hyperalgesia [48,59]. It is noteworthy, that the functional changes in CRPS [49] and in phantom pain [22]
were dynamic, i.e. cortical reorganization reversed coincidently with clinical improvement. Currently, chronic
pain states are attributed to abnormal nociceptive/antinociceptive function on dierent levels of the neuroaxis
[75] with a normal brain structure. However, any
signicant challenge that requires a specic function,

0304-3959/$34.00 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2008.02.034

A. May / Pain 137 (2008) 715

including learning a specic task, has the potential to

alter brain structure [55]. Given that the initiation of
chronication of pain involves nociceptive input, one
would expect that neuroplasticity would probably occur
in modulatory areas of nociception namely, the antinociceptive system.
Two fundamental questions arise:

Imunology

cognitive changes

functional

autonomic nerve system

structural

supraspinal

 Is there any evidence that humans suering from

chronic pain show altered brain morphology in structures related to the perception and behavioral
response to pain, such as the thalamus, insulae, sensorimotor and cingulate cortices and the antinociceptive descending pathways?
 Is this alteration the cause or the consequence of
chronication?

Modulation and modification of nociceptive and

antinociceptive synaptic transmission

spinal
Central sensitization, long-term potentiation, disinhibition

2. Plasticity in chronic pain

Plasticity is a term used to refer to changes that occur
in the established nervous system. The last decade has
unraveled some of the mysteries of chronic pain and
has clearly demonstrated that neuroplasticity at several
levels of the nervous system is related to the propagation
of pain long after the original cause is gone, depriving
pain of its functional role and becoming the disease
itself. Neuroplastic changes relating to function, chemical prole, or structure during the process of pain chronication have been described for both, the peripheral
(receptor and ion-channel reorganization, neurotransmitter changes) and cerebral nervous systems (functional changes of representational elds) including the
spinal cord (sensitization and disinhibition) as well as
the dynamic interaction of all these levels with the
immune system and higher cognitive functions. Fig. 1
summarizes the dierent levels of plasticity in pain
known so far. However, this meta-analysis will focus
on the most recent studies using structural brain imaging in chronic pain patients and will not cover the other
neuronal systems that have already been considered in
excellent reviews [25,40,50,70,80].
3. Structural brain imaging
In the past, studies of brain morphology completely
depended on autopsy material. This situation changed
with the advent of modern in vivo imaging methods, in
particular, magnetic resonance (MR) imaging. All quantitative MR-based methods are subsumed under the
heading of MR morphometry of the brain and are based
on the idea of using a common coordinate system or
atlas. Normally, three-dimensional, high-resolution,
T1-weighted MRI images acquired with conventional
1.5 T MR scanners and 1 mm3 voxels provide sucient
detail and contrast [5] whereas scanners with higher eld

peripheral
Peripheral sensitization, denervation, ectopic activity

Fig. 1. Dierent levels of plasticity in chronic pain. Neuroplastic

changes (change in function, chemical prole or structure) during the
process of pain chronication have be distinguished on the level of the
peripheral, spinal and cerebral nervous system [25,40,50,80].

strength (3 T, 7 T) allow for higher spatial resolution.

Images from several subjects can be grouped together
and analyzed by mapping them onto a standardized
coordinate space. Voxel-based morphometry (VBM) is
the most commonly applied technique. It is relatively
simple to use, has moderate demands on computational
resources and is available in common software packages
like FSL [28,71] or SPM [27] (Table 1).
As a non-invasive procedure, MR morphometry is
the ideal tool for nding the morphological substrates
of diseases, deepening our understanding of the relationship between brain structure and function, and even to
monitor therapeutic interventions. It has to be said that
most studies focus on cohort or cross-sectional studies,
leading to the question of cause and consequence.
Important contributions to the exact causes of structural
changes will come from studies that look at the time
parameters of these changes and include independent
factors (i.e. electrophysiology or genetics). Moreover,
the exact cause of lesion- and training-related morphological changes in the adult brain is still not known. A
decrease in the brain gray matter, such as has been
described in chronic pain patients, does not necessarily
mean neuronal destruction. Potential correlates of the
observed morphometric changes include a simple
change in cell size, shrinkage or atrophy of neurons or
glia, as well as changes in the intra-cortical axonal architecture (synaptic loss) [54]. The analysis of the cortical

p
p

p
p
p
p
p
p

28
18
20
16
27
18
28
10
20
35
24
11
[51]
[3]
[68]
[65]
[74]
[67]
[15]
[43]
[69]
[66]
[8,32]
[9]
Migraine (VBM)
Chronic back pain (VBM)
CTTH(VBM)
Frequent Migraine (VBM)
Frequent Migraine (VBM)
Chronic back pain (VBM)
Phantom Pain VBM)
Fibromyalgia (VBM)
Fibromyalgia (VBM)
Frequent Migraine (VBM)
Frequent Migraine (DTI)
IBS (VBM and DTI)

Note that a change in any region (e.g. decrease in cingulate cortex) can anatomically dier between studies. These dierences could be due to scanner eects, dierent preprocessing and analysis of
the data or dierent phenotypes of the subjects scanned. CTTH, chronic tension type headache; IBS, irritable bowel syndrome.

p
p
p

p
p
p

Insula cortex
decrease
Orbito-frontal
cortex decrease
S1
increase
Thalamus/basal
ganglia increase
Thalamus/basal
ganglia decrease
Brain stem
increase
Brain stem
decrease
Cingulate
cortex increase
Cingulate cortex
decrease
No of
subjects
Reference

Table 1
Findings of changes in gray matter in dierent studies using voxel-based morphometry (VBM) or diusion tensor imaging (DTI), investigating chronic pain patients and comparing them to healthy
volunteers

A. May / Pain 137 (2008) 715

surface complements these voxel-based methods. For

these approaches, the cortical surface is extracted from
brain scans and further computations are applied then
to calculate parameters such as cortical thickness [19]
or complexity [73]. More recently, this has also allowed
the local three-dimensional computation of the gyrication index as a measure of the degree of folding of a
given cortical area [47]. An advantage over VBM and
DBM is the improved reduction of inter-subject variability in cortical folding patterns [4]. However, the
extraction of the cortical surface imposes high demands
on computational resources and crucially depends on
the quality of surface extraction, which sometimes
requires additional manual correction or interaction.
Notwithstanding these limitations, with the development of novel computational techniques during the last
few years and increasing image resolution, the era of
MRI-based morphometry has begun to expand. Recent
ndings and further methodological developments
should lead to scientic breakthroughs that will change
how we think of the brain. Following is a summary of
the most recent of these developments with regard to
chronic pain.
4. Chronic back pain
In many countries, chronic back pain is one of the
most frequent pain disorders in the general population.
7085% of all people have experienced back pain at
some point in their lifetime [2]. Nevertheless, the mechanisms of chronication are the subject of intense
research and debate. The pioneering work by Apkarian
et al. using sophisticated morphometric analysis methods in 17 patients suering from chronic back pain demonstrated brain atrophy and suggested that the
pathophysiology of chronic pain includes thalamo-cortical processes [3]. Specically, this study found a decrease
in gray matter in the dorsolateral prefrontal cortices
(DLPFC) bilaterally and a decrease in gray matter in
the right thalamus. The authors suggested that neurodegeneration rather than tissue shrinkage without a
substantial impact on neuronal properties may be the
cause of this nding. This study was in part replicated
by Schmidt-Wilcke et al., who investigated 18 patients
with matched healthy controls and also found a decrease
in gray matter in the DLPFC. However, this study also
found an increase in thalamic gray matter and an additional decrease in the dorsolateral pons and the somatosensory cortex [67]. Interestingly, the correlation
analyses suggested that the gray matter decrease in the
brainstem does not correlate with pain duration, but
rather with pain intensity and pain unpleasantness experienced at the time of scanning, thus possibly accounting
for the degree of impaired antinociception at that time.
The dierences between the studies by Apkarian et al.
and Schmidt-Wilcke et al. are not easy to interpret.

10

A. May / Pain 137 (2008) 715

One explanation is the relatively small sample sizes used

in these studies, so that negative ndings have little
meaning. However, Schmidt-Wilcke et al. only included
patients without radiating pain, including radiculopathy, whereas Apkarian studied a mixture of patients
with and without neurological manifestations as well
as patients with pain outside of his region (for example,
in the upper back). In summary, chronic back pain is
accompanied by specic morphological alterations in
structures known to play a crucial role in antinociception, which may correlate to the intensity and unpleasantness of pain.
5. Phantom pain
At least in primates, plasticity in the adult brain can
occur rapidly as a consequence of peripheral lesions and
sensory deprivation [61]. Cortical reorganization on a
functional level, as revealed by neuromagnetic and neuroelectric source imaging as well as functional MRI and
PET, has been found to correlate with a massive expansion of adjacent cortical representational areas following
limb deaerentation in monkeys and humans
[13,23,46,76,77]. Functional reorganization following
amputation has been described in the primary somatosensory cortex, which was suggested to correlate with
painful, but not with non-painful phantom sensations
[17,23,34]. For non-painful phantom sensations, the
suggested candidate structures for plasticity changes
are the thalamus, posterior parietal and prefrontal cortices as well as the secondary motor cortex [13]. These
ndings led to the concept of maladaptive plasticity
challenging the assumption of an obligatory benecial
eect of functional plasticity in terms of adaptation
and recovery of function after lesion of the nervous system with loss of aerent input.
However, only a few studies have examined structural
alterations in the primate brain following limb amputation (for review see [38]). Several postmortem studies
claim to have identied the anatomical correlates as a
consequence of a loss of aerent input. Considering
the results of two recent histopathological studies on
primates after limb deaerentation, there are dierent
possible anatomical locations in the adult human brain
where structural changes could occur. It was demonstrated that long-standing limb amputation can cause
structural reorganization of the brainstem, thalamic
nuclei or the somatosensory cortex [26,39].
To test the hypothesis, whether the loss of aerent
input can structurally alter the adult human brain, we
applied voxel-based morphometry (VBM) on structural
MRI scans of 28 unilateral amputees and 28 corresponding age- and sex-matched controls [15]. This study
demonstrated a specic gray matter reduction in the
postero-lateral thalamus in patients with a traumatic
upper/lower limb amputation compared to healthy vol-

unteers. A positive correlation between these structural

variations and time since amputation [15] supports the
assumption that these alterations may occur as a consequence of chronic absence of behaviorally relevant
information. Interestingly, phantom limb pain as a
covariate failed to show thalamic dierences and demonstrated subtle structural alterations, i.e. a decrease
in gray matter in brain areas involved in pain processing
and modulation, such as the anterior and posterior cingulate cortices as well as the SMA and dorsal mid-brain.
These data support the concept of maladaptive plasticity and accordingly may reect some of the cortical
somatosensory pain memory, whose subjective features have been described by Katz and Melzack [41].
6. Chronic head pain
Chronic daily headache (CDH), dened as headache
occurring on 15 or more days per month [78], is a frequent disorder. The most frequent subtypes are chronic
tension type headache (CTTH) and medication overuse
headache (MOH) [37]. Whereas CTTH is still dicult to
treat, MOH shows distinct improvement after medication withdrawal. Given that patients with cluster headache [53] or migraine [65] have subtly dierent brain
structures, the question arises whether the distinct subtypes of CDH may also be distinguishable on a morphometric level. Using VBM in 40 CDH patients (20 chronic
tension type headache patients and 20 medication overuse headache patients according to the International
Headache Society criteria [37]) and comparing them
with healthy controls, only CTTH patients showed a signicant decrease in gray matter in the dorsal rostral and
ventral pons, the perigenual ACC (BA 24), mid-ACC
(BA 24/31) and right PCC (BA 23), the anterior and
posterior insulae bilaterally, the right posterior temporal
lobe, the orbito-frontal cortex and parahippocampus
bilaterally and the right cerebellum [68]. This decrease
in gray matter correlated positively with increasing
headache duration in years, i.e. patients with longer history had less gray matter in these regions. The fact, that
this change in gray matter in CTTH patients mainly
involves structures involved in pain processing could
reect either the cause or the consequence of chronic
head pain. At the moment, these data suggest that while
CTTH and MOH may share some common features, i.e.
frequent head pain, the underlying pathogenesis diers
signicantly, as inferred from the dierent clinical patterns of pain characterization and responses to
treatment.
7. Migraine
Functional imaging of headache has demonstrated
that neuronal activation patterns in primary headache
syndromes fall into two groups: areas known to be gen-

A. May / Pain 137 (2008) 715

erally involved in pain processing, such as the cingulate,

insular cortex and thalamus, and areas activated specifically in primary headache such as the hypothalamus in
cluster headache attacks [53] and the brainstem in acute
migraine [1,52]. These regions are not thought to be
involved in the response to pain stimuli, but seem to
play a permissive, possibly even a causative role, which
supports the idea of an underlying neurovascular rather
than purely vascular mechanism. Regarding surfacebased methods, a very recent study described structural
abnormalities in the network of motion-processing areas
which could account for the cortical hyperexcitability
observed in migraineurs [32]. The same group showed
in the same group of patients that migraineurs may have
a thicker somatosensory cortex (S1) than the control
group [8]. Both ndings are highly interesting and demonstrate the future potential impact of these methods on
our pathophysiological concepts of pain and headache.
Regarding voxel-based morphometric analysis
(VBM) of structural T1-weighted MRI scans, cluster
headache patients show a colocalization of morphometric alterations and functional activation [53]. A pioneering study by Matharu et al. did not nd any signicant
morphometric changes in gray or white matter in
patients suering from episodic migraine [51], whereas
patients with chronic tension type headache showed a
decrease in brain gray matter in several pain-transmitting structures [68].
Three recent studies question the ndings by
Matharu et al. The rst one was published by Rocca
et al., who investigated 16 migraine patients and
reported reduced gray matter density in the anterior cingulate cortex, anterior insulae and temporal lobes [65].
They also described increased density of the PAG and
of the dorsolateral pons in migraine patients [65]. The
second study investigated 35 patients suering from
migraine and compared them to 31 healthy controls
with no headache history. The third study investigated
27 migraine patients and compared them to 27 healthy
controls [74]. Using MRI and voxel-based morphometry
(VBM), both studies reported a signicant decrease in
gray matter in areas ascribable to the transmission of
pain (cingulate cortex), but not in areas specic for
migraine, such as the brainstem [66]. One possibility
for this discrepancy is the fact that the Matharu study,
the Valfre study as well as the Schmidt-Wilcke study
used a 1.5 T scanner, whereas the Italien group used a
higher eld strength (3 T), which may be an advantage
in detecting subtle dierences in cohort studies. However, the migraine cohort of the Italien group was rather
small (16 patients) and comprised only patients with T2visible brain lesions, a nding which is not part of the
IHS criteria and moreover, rather unusual in migraine
patients. As migraine has a strong genetic component,
the ideal inclusion criteria for future studies to render
groups as homogeneous as possible could be based on

11

genotype (cohort study) or response to treatment (longitudinal study including controls).

Although the main nding by Rocca et al. is very similar to our ndings (decrease of gray matter in paintransmitting structures), our interpretation of the results
is dierent. Rocca et al. suggested that gray matter
changes may be the consequence of repeated brain insult
or damage during migraine attacks [65]. According to
their interpretation, the topographical distributions of
gray matter changes would be the consequence of cortical regions having varying susceptibilities. This mechanism was discussed to be facilitated by a retrograde
degeneration of axons passing through T2-visible lesions
of the white matter, which was an inclusion criterion in
the above-mentioned study. However, a striking feature
of both studies is the fact that the gray matter changes
were not randomly distributed, but concerned dened
and functionally highly specic brain areas namely,
involvement in supraspinal nociceptive processing. It is
indeed remarkable that the alterations (i.e. decrease in
gray matter) seen in the anterior cingulate cortex in
migraine patients are similar to a decrease in this region
in chronic back pain [67] and chronic phantom pain [15].
As most changes correlate 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. 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.
8. Fibromyalgia and irritable bowel syndrome
Primary bromyalgia is a common yet poorly understood syndrome characterized by diuse chronic pain
accompanied by other somatic symptoms, including
poor sleep, fatigue, and stiness. The study of chronic
pain has yielded new insights into the pathophysiology
of bromyalgia and related chronic pain disorders, suggesting that bromyalgia may be associated with a central nervous system dysfunction [12,31]. A very recent
work by Kuchinad and coworkers examined, using morphometric methods, the brains of 10 female bromyalgia
patients and 10 healthy controls. Despite the relatively
low numbers, they found a reduction in regional gray
matter in the left parahippocampal gyrus, bilateral
mid/posterior cingulate gyrus, left insula and medial
frontal cortex [43]. Just like in most other studies investigating gray matter dierences between chronic pain
patients and healthy controls, no areas with a signicant
increase in gray matter were found. Another study
found a decrease in orbitofrontal structures as well as
a striatal gray matter increase in patients suering from
bromyalgia [69]. A very recent study investigated
patients with irritable bowel syndrome (IBS) using

12

A. May / Pain 137 (2008) 715

VBM and surface-based methods [9]. Using a cortical

thickness analysis (CTA) algorithm, implemented in
BrainVoyager QX, the authors describe a signicant
cortical thinning in the patients with IBS which was
localized to the right ACC and the anterior insula bilaterally. Moreover, the authors found, using VBM,
reduced gray matter in the rostral ACC (BA32) and
the anterior/medial thalamus in the IBS group relative
to healthy controls. These ndings show a remarkable
overlap with the above-mentioned ndings in other
chronic pain syndromes, suggesting a common basis.
Notably, these ndings also relate to functional changes
found in fMRI studies in those patients [45].
9. Do chronic pain patients have a common brain
signature?
All eight morphometric studies in chronic pain
together suggest that the concept of central structural
plasticity is important for an understanding of chronic
pain. As neither pain-related inactivity [15], nor pain
medication [3,43,68] explains this nding, the in vivo
demonstration of a loss of brain gray matter in patients
suering from chronic pain compared to age- and sexmatched healthy controls could represent the heavily
discussed neuroanatomical substrate for pain memory.
All studies but one showed structural alterations in specic brain areas referred to as the pain matrix. These
alterations were dierent for the dierent pain syndromes, but, in terms of functional systems, overlapped
to an astounding extent (Fig. 2). Irrespective of the location, nature or course of the dierent pain syndromes,
the most common nding is a decrease of gray matter
in the cingulate cortex, the orbitofrontal cortex, the
insula and the dorsal pons, suggesting a common basis.
It is, however, crucial to stress that this phenomenon,
which coincides with the chronication of pain does
not act in isolation. It inuences and is inuenced by
nociceptive and spinal events. The plasticity and
dynamic interaction among nociceptors [80], neurotransmitters [42], glial, neuronal and endothelial cells
[30], receptive elds [72] and the immune system [50]
as well as higher cognitive functions [24,35] needs to
be considered. They comprise a complex collection of
many discrete, but interacting, systems [56]. However,
although the complexity of pain perception involves
many levels of the neuraxis, cortical plasticity is certainly not restricted to functional changes.
The data indicating that the cingulate cortex is
aected in chronic pain raise some speculation on the
neuronal pathways of chronic pain. The anterior cingulate cortex and the anterior insulae function as multiintegrative structures during the experience and the
anticipation of pain [58,62]. The anterior cingulate
cortex, including the perigenual part, is of particular
interest, since it plays a deterministic role in pain modu-

Fig. 2. Statistical parametric maps demonstrating the structural

dierence in gray matter between chronic pain patients and unaected
control subjects. Signicant gray matter decrease is shown for each
single group of patients, compared to matched healthy controls and is
superimposed in yellow color on a normalized image of a healthy
control subject. (Top row left) Phantom pain (n = 28) [15]; (top row
right) tension type headache (n = 20) [68]; (lower row left) chronic
back pain (n = 18) [67]; (lower row right) frequent migraine without
aura, (n = 35) [66]. Similar ndings have been found in bromyalgia
[43]. The gray matter changes found in all chronic pain syndromes
suggest a common pattern which may implicate the process of not only
primary, but also secondary transneuronal degeneration due to
chronic aerent input.

lation and analgesia. The analgesic/modulating eect is

mediated through the interaction with other structures,
such as the orbitofrontal cortex, the amygdala and the
PAG [81]. All of these structures also showed alteration
in some of the studies mentioned here. The collective
evidence for the rACC as a crucial site for endogenous
pain control has been observed in the context of pain
modulation by attention, anticipation of pain and placebo analgesia [6,18,57,60,63,64] (for a review see [44]
and also studies of neurostimulation for pain relief [10]).
The brainstem is another anatomical site which is
linked to antinociception. In humans, stimulation of
the brainstem is suggested to be eective in intractable
pain states [16,36] and in functional imaging studies an
activation in the mesencephalon following the application of pain stimuli has been frequently described
[11,58]. Recently, evidence has been provided that iron
levels in the PAG might be abnormally high in migraine
patients [79], correlating with disease burden.
The decrease of gray matter in brain regions which
are highly associated with pain suppression could certainly lead to dysfunction in eective antinociception.
Abnormal modulation of brain nociceptive systems, at
rst transient, but becoming permanent with continuing
illness, could in part explain the shift from acute to

A. May / Pain 137 (2008) 715

chronic pain. Very recently, and using a dierent methodological approach, Karen Davis et al. were able to
show that patients suering from irritable bowel syndrome (IBS) show a signicant cortical thinning of the
ACC, a nding which has striking similarity to the ndings discussed above [9].
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 specic brain areas. This
question is not redundant, as a degenerative process is
irreversible. Although many VBM studies demonstrate
changes in gray matter, the neurobiological basis of
these structural alterations on a microscopic level is
not well dened [54]. VBM detects changes in gray matter concentration per voxel as well as changes in the classication of individual voxels, e.g. from white to gray
matter [29] and probably a combination of both. In general, a decrease in gray matter could be due to a simple
decrease in cell size, neural or glial cell apoptosis, a
decrease in spine density or even changes in blood ow
or interstitial uid. Unfortunately, all available studies
compared cohorts of patients and therefore no statement regarding dynamic changes can be made.
10. Central plasticity: cause or consequence?
It is not understood why only a relatively small
proportion of humans develop a chronic pain syndrome, considering that pain is a universal experience. As the adult human brain may change its
structure in response to environmental demands
[14,55], the question arises whether in some humans
a (possibly genetically) structural dierence in central
pain-transmitting systems may act as a diathesis for
chronic pain. In the course of chronication, numerous modulatory mechanisms, such as eects at the
nociceptor level, sympathetically mediated pain, the
wind-up phenomenon, central sensitization, and
changes in descending and ascending central modulatory mechanisms for the perception of pain have
been postulated and altogether addressed as neuronal plasticity [80]. The recent data referred to in this
article suggest that structural changes of the brain
may be added to this list. Considering chronic pain
as a result of maladaptive plasticity argues against
the assumption that functional plasticity in terms of
adaptation and recovery of function after lesion to
the nervous system [25] is necessarily benecial. There
are no conclusive data regarding the cause or the
consequence of the dierent cortical and subcortical
morphological changes, although the correlation of
pain duration and degree of gray matter decrease in
most studies suggests that the morphological changes
are at least in part secondary to constant pain. It is a

13

challenge for future studies to address this crucial

question. The idea of structural maladaptive plasticity, however, serves certainly well as a good model
for structural cortical/subcortical reorganization following chronic input of nociceptive information.
11. The challenge for future studies
We do not know what exactly causes the observed
decrease in regional gray matter shown in all the studies. Possible explanations include a simple decrease in
cell size, cell atrophy or a decrease in the intra-cortical
axonal architecture (i.e. synaptic loss). Important contributions to the exact causes of the structural changes
will come from studies that look at the time parameters
of these changes and include independent factors (i.e.
electrophysiology or genetics). The ndings discussed
here are not precisely consistent across all studies (for
example changes in dierent parts of the cingulate cortex). These dierences could be due to scanner eects,
dierent preprocessing parameters or analysis of the
data and nally dierent phenotypes or genotypes of
the subjects scanned. One of the key questions is
whether structural alterations in the pain matrix precede or succeed the clinical process of chronication.
Thorough longitudinal studies need to address whether
the morphological changes reverse when the disproportionate amount of nociceptive stimulation (i.e. following sucient pain treatment) stops. Another crucial
question is, whether, analogue to functional studies
demonstrating a dynamic response to frequent nociceptive input [7] a repeated painful stimulation over several days changes the structure of the healthy human
brain. It may well be, that the brain of a healthy control shows a healthy response such as habituation
and increase of respective brain structures, whereas
the brain of a chronic pain patient shows a dierent
or even diametric response. Together, these studies
could answer the question whether the above-mentioned morphometric alterations are the cause or the
consequence of chronic pain. Modern neuroscience
faces the challenge of unraveling the complex regulatory mechanisms underlying short- and long-term neuronal reorganization, which can follow changes in the
environment throughout life.

Acknowledgments
The author acknowledges the important contributions to the recent structural imaging studies in phantom
pain, back pain and headache from B. Draganski and
T. Schmidt-Wilcke and thanks E. Schoell, U. Bingel
and C. Buechel for reading the manuscript. A. May
was supported by a grant of the Deutsche Forschungsgemeinschaft (MA 1862/2). This study was supported

14

A. May / Pain 137 (2008) 715

by a grant of the Federal Ministry of Education and Research (BMBF project no. 371 57 01).
The author has no conict of interest.

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