J Headache Pain (2004) 5:204208
DOI 10.1007/s10194-004-0103-0BRIEF REPORTSheena K. Aurora
Vijaya NageshK. Michael A. WelchFunctional imaging of subcortical nociceptive
structures in response to treatment of chronic
daily headacheAbstract The objective was to provide objective imaging evidence of
functional changes in brainstem
structures involved in chronic daily
headache (CDH). Over time, episodic migraine (EM) patients may
develop CDH known as transformed
migraine (TM). Using analysis of
transverse relaxation rates, R2, R2*
and R2 (R2* values are reflective of
blood oxygen level dependence; R2
is a measure of non-heme iron in tissues) we have reported activation
(hyperoxia) of red nucleus (RN) and
substantia nigra (SN) (decreased R2*
and R2) in CDH patients studied
during headache, and dysfunction of
periaqueductal grey (PAG) based on
increased iron levels (elevated R2)[1]. We now report a patient with
CDH who, upon treatment, reverted
to EM, permitting studies when
headache free and an objective
analysis of treatment response. SP is
a female aged 48 years. She presented with daily headaches for 6
months. Episodic headaches, meeting
IHS criteria for migraine without
aura, began in her 20s. At the time of
presentation she was taking 5 tablets
of ergotamine tartarate in the form of
Ercaf and 6 extra-strength acetaminophen daily. Repeated dosages of
intravenous dihydroergotamine for
three days during withdrawal of all
medications successfully achieved
clinical reversion from CDH to EM.
She was studied both during CDH
and when headache free after reverting to EM, using high-resolution MR
techniques to map the transverse
relaxation rates R2, R2* and R2 in
RN, SN and PAG. For technical reasons, PAG was not imaged during
the CDH phase of her illness. During
the CDH phase of her illness, respective R2* values were reduced compared to normal in the RN and SN to30.1 m/s and 31.45 m/s. Similarly,
R2 in RN and SN were abnormally
low at 6.62 m/s and 6.72 m/s compared to normal. Subsequent
headache free studies demonstrated
that R2* and R2 in the RN became40.1 m/s and 15.47 m/s respectively,
and in the SN, 40.25 m/s and 15.19
m/s respectively. These values were
similar to EM patients and normal
controls. The R2 in PAG during EM
for this subject was increased at 6.88
m/s but elevated compared to controls. Daily headache in this patient
was associated with chronic activation of pain networks that included
RN and SN. Resolution of headache
was associated with resolution of
activation, although there was evidence for persistent PAG dysfunction, as previously reported. To the
best of our knowledge, this case represents the first objective correlation
of functional changes in brainstem
nociceptive networks with clinical
features of TM and its response to
treatment.Key words Daily headache
Functional neuroimagingReceived: 2 December 2003
Accepted in revised form: 24 May 2004S.K. Aurora ()Swedish Headache Center,
1221 Madison, Suite 1026,
Seattle, WA 98116, USA
e-mail: [email protected]
Tel.: +1-206-215-2243
Fax: +1-206-215-2245V. NageshDepartment of Neurology,
Henry Ford Hospital,
Detroit, MI, USAK.M.A. WelchOffice of the President,
Finch University of Health Sciences,
The Chicago Medical School,
Chicago, IL, USA205Chronic daily headache (CDH) is a descriptive term used for
a heterogenous group of conditions which has headache on a
daily or an almost daily basis as a common feature [1]. The
new International Headache Society (IHS) to date has
accepted a uniform classification, similar to the one that had
been proposed by Silberstein et al. [2]. Within this latter classification chronic migraine is regarded as the most prevalent.
The underlying mechanisms of chronic migraine are not well
known but medication overuse has been described implicitly
with the popular term transformed migraine [3]. We
imaged a subject with chronic migraine in order to investigate the underlying mechanism. There has been an increasing body of evidence for involvement of nociceptive pathways in CDH and migraine. The first reports came from
Raskin et al. who observed a migraine-like headache develop in patients with electrode implantation in the PAG [4]. In
a single case report a discrete sclerotic lesion in the region of
the PAG in a patient with multiple sclerosis caused severe
headache [5]. Recently, a brainstem lesion in the area of periaqueductal grey (PAG) in a patient with CDH has been
described [6]. The patient had no previous history of
headache and developed new daily persistent headache and
on MRI a cavernous angioma was noted in the region of the
PAG. In addition there has been a recent report of two members of a family with cavernous angiomas and mutations in
chromosome 7q who had chronic migraine with angiomas in
the upper brainstem as compared to other family members
without chronic migraine who had supratentorial lesions [7].
On PET imaging other brain stem structures in addition to the
PAG i.e., dorsal raphe nuclei (DRN), and locus ceruleus (LC)
were activated during migraine [8]. We have reported activation of the red nucleus (RN) and substantia nigra (SN) during a spontaneous migraine attack [9]. We followed that by
reporting a disturbance of function in the PAG, RN and SN
in patients with CDH and migraine [10]. We observed
increased tissue iron levels in the PAG of episodic migraine
(EM) with and without aura and CDH sufferers. The iron
deposition in these nociceptive structures correlated directly
with duration of the disorder. We now report a case of CDH
that reverted to EM after repeated dosages of intravenous
dihydroergotamine and the changes that correlated on neuroimaging of the nociceptive pathways.MethodsCase reportSP is a female aged 48 years. She presented with daily headaches
for 6 months. She had a history of episodic headaches, which met
the International Headache Society (IHS) criteria for migraine
without aura. The EMs began in her 20s and the usual triggers
were eating chocolate or her menstrual periods. At the time of
presentation she was taking 5 tablets of ergotamine tartarate in
the form of Ercaf and 6 extra-strength acetaminophen daily. The
ergotamine tartarate and acetaminophen were withdrawn and the
patient was treated with repeated dosages of intravenous dihydroergotamine (I/V DHE) for three days. This was done following the Raskin protocol of administering 1 mg I/V DHE every 8
hours [11]. On the second day the patient became headache free
and subsequently reverted to EM. The patient was imaged twice,
first in the interictal period during her CDH and then three
months later when she reverted to EM phase.TechniquesAll MR images were acquired with a 3 Tesla, 80-cm (inner diameter) magnet (Magnex Scientific, Abingdon, England) with a
maximum gradient strength of 18 mT/m and 250 s ramp time. A
quadrature birdcage head coil was used for imaging. Spin-echo
sagittal images were obtained to align the imaging plane so that
it was parallel to the plane encompassing both the inferior colliculus and mammillary body.Multi-slice measurements of R2, R2 and R2* were performed in a single acquisition using the gradient-echo sampling
of free induction decay and echo (GESFIDE) sequence [12]. The
timing of the echoes in this sequence was identical to those used
previously [13]. Briefly, two slice-selective 90 and 180 radiofrequency (RF) pulses were used in this sequence. Five gradient
echoes were acquired between the 90 and 180 RF pulses, followed by acquisition of six echoes after the 180 pulse. The final
echo produced a spin-echo at 98 ms. Sixteen thin contiguous 2.2
mm slices from the ponto-medullary border to slightly above the
superior border of the putamen were obtained within 10.7 min. A
128x128 imaging matrix with a 220 mm field of view, and 2500
ms repetition time was used for image acquisition. Even and odd
slices were obtained in separate scans to avoid interference from
adjacent slices. The imaging time of the entire protocol, inclusive
of positioning and shimming was approximately 20 min.Image analysisThe image sets were Fourier transformed and zero-filled to yield
256x256 in-plane images for each of the 176 two-dimensional
images (16 slicesx11 echoes). Maps of R2, R2 and R2* were
obtained as described in previous studies [13]. The procedure
involved construction of R2* maps from the first five echoes and
R2- (=R2-R2) maps from the last six echoes of the GESFIDE
sequence [12]. Further, the R2* and R2- maps were converted to
R2 and R2 maps using the expressions given below:R2=(R2*+R2-)/2R2=(R2*-R2-)/2Brain tissue segmentation was performed using the Iterative
Self-Organizing Data Analysis Technique (ISODATA) clustering
technique [14]. ISODATA is a semi-automated algorithm based on
techniques of multivariate statistical analysis. The algorithm is206based on Euclidean measures of pattern similarity. A vector feature
is constructed at each spatial location from the set of input data.
The clusters are determined in such a way that the intra-set distance
in each cluster is kept to a minimum, and the inter-set distance
between two clusters is made as large as possible. The number of
source images determines the dimension of the Euclidean (feature)
space in which the clustering is carried out. To improve tissue
specificity, qualitatively different images were used to increase the
likelihood of separating two tissues with similar signature profiles.All image slices were reconstructed from the final echo
(TE/TR=98/2500 ms) of the GESFIDE sequence and were then
reviewed visually to identify and localise slices containing the PAG,
RN and SN. The RN and SN were visible in two or more slices in
this case. In this subject, the PAG region was imaged and clearly
delineated during CDH, but during the EM phase; PAG could not be
clearly delineated due to technical difficulties encountered during
that scan. ISODATA segmentation was used to accurately delineate
and identify the entire volume of the PAG, RN and SN. Eleven
images (one from each echo of GESFIDE sequence) were used as
source images for the ISODATA segmentation of each slice. This
technique ensured that anatomic borders were not crossed. An operator classified the resulting zones into grey matter, white matter,
cerebrospinal fluid (CSF), PAG, RN and SN. For each subject, the
R2 (1/T2), R2* (1/T2*) and R2 (1/T2*1/T2) relaxation rates of
the RN, SN and PAG were obtained for the left and right sides separately by projecting the corresponding segmented zones onto the
maps. Measurements derived from multiple slices for this subject
were expressed as a weighted average during both the CDH and EM
phase and compared to the normal values previously reported.ResultsThe range of values for R2* in 17 normal subjects for RN
and SN ranged from 39.12.85 m/s, SN=42.53.01 m/s,
respectively [10]. During the CDH phase of her illness,
respective R2* values were reduced compared to normal in
the RN and SN to 30.1 m/s and 31.45 m/s (Fig. 1). Similarly,
R2 in RN and SN were abnormally low at 6.62 m/s and 6.72
m/s compared to normal (RN=14.32.18 m/s, SN=15.12.20
m/s) (Fig. 2). Both indices indicated prominent activation
(increased flow and hyperoxia) of these structures during
headache. (A decrease in R2* and R2 reflect the influence of
free iron from deoxyhaemoglobin.) Subsequent headache
free studies demonstrated that R2* and R2 in the RN
became 40.1 m/s and 15.47 m/s respectively, and in the SN,40.25 m/s and 15.19 m/s respectively (Fig. 2). These values
were similar to EM patients (R2* and R2 in the RN39.13.07, 13.81.86 and SN 42.23.27, 15.01.94) and
normal controls. No differences were found in the R2 values
of SN and RN during any phase or overall between CDH,
EM and controls. The R2 in PAG during EM for this subject
was increased at 6.88 m/s (mean for EM=6.110.88, n=17)
but elevated compared to controls (4.330.97 m/s, n=17).Fig. 2 R2 values for the RN and SN of the patient during CDH and
then increased values similar to controls during EMFig. 1 R2* values for the RN and SN of the patient during CDH and
then increased values similar to controls during EM207DiscussionTo our knowledge this is the first case report in which a
patient has been studied using functional neuroimaging during CDH and EM. This paper has the shortcoming of being
an isolated case report and needs further study. Nevertheless,
the RN and SN both showed dynamic changes of activation
as measured by increased flow and hyperoxia during the
CDH phase with normalisation during EM. We can therefore
hypothesise that the analgesic overuse led to dynamic
changes of activation in these structures. The changes
demonstrated during the CDH phase are not likely the result
of active pain as that would have resulted in opposite values
of the R2. We are not able to determine exact reasons for
these changes although it may be hypothesised that daily
medication use may have led to changes in blood flow. The
RN and SN have hitherto been best known for their functional roles in motor control. We have previously published
an isolated case report which found RN and SN to be activated in a spontaneous migraine attack [9]. We have since
reported the RN and SN to be activated in the subjects with
visually triggered migraine [15]. The RN has also been associated with pain and/or nociception [16]. Numerous animal
studies have documented a response of RN neurons to a variety of sensory and noxious stimuli [17]. In a PET study performed on normal volunteers during capsaicin induced pain,
ipsilateral activation of RN was documented [18]. It remains
to be clarified whether or not the RN is involved in the pain
pathways or in the motor response to pain. Future studies will
need to address whether this activation is a result of generalised pain or exclusively sensitive to headache.The PAG unfortunately could not be clearly delineated
during CDH but showed an increased iron deposition during EM. This is in keeping with our previous finding that
iron homeostasis is selectively, permanently and progressively impaired in the PAG indicative of a permanent dysfunction in EM [10]. The study however has an advantage
of showing dynamic changes and values during CDH and
EM were similar to our previous report with several
patients. In addition, this study provides an explanation for
the previously well-documented clinical implications of
chronic migraine secondary to analgesic overuse.The midbrain PAG is an anatomically heterogeneous,
functionally diverse region of densely layered neurons surrounding the aqueduct of Sylvius [19]. Receiving input
from the frontal cortex and hypothalamus, and projecting
to the rostral ventromedial medulla thence to the medullary
and spinal dorsal horn, the PAG is the centre of a powerful
descending antinociceptive neuronal network. During
migraine the PAG was shown to be hyperactive in PET
studies [8]. The ventrolateral subdivision of the PAG is of
particular importance to the trigeminal nociceptive modulation [20].Further, the PAG can be considered a major nodal point
in the central nervous system (CNS), regulating autonomic adjustments to antinociceptive, autonomic and behavioural responses to threat. In animal experiments the PAG
has been shown to be intimately involved with analgesia[21]. The dysfunction of PAG in migraine may explain
why overuse of analgesics in EM is likely to result in
CDH. This has been demonstrated in population-based
studies and in a recent systematic study performed on a
group of subjects using chronic analgesics for arthritis[22]. It could be therefore hypothesised that analgesics,
because of selective action on specific brain sites i.e., PAG[23], produce a reaction in the form of CDH due to a dysfunctional PAG in migraine.No genetic studies have been performed in CDH, however patients with a family history of primary headache
disorders are more likely to be predisposed [24]. A genetic
link to the predisposition of hyperactivity in the nociceptive system in migraine was recently established [25].
Using a microinjection of the P/Q channel blocker -agatoxin IVA into the vlPAG, a facilitation was noted in the
trigeminal nociceptive activity. This study demonstrated
the influence of both the P/Q-type calcium channels and
PAG in trigeminal pronociception.The development of CDH from EM has been associated
with other implications besides analgesic overuse.
Depression and anxiety are more common in CDH and lifeevents have been associated with the transformation of EM
to CDH. In a recent study CDH sufferers were more likely
to have had a history of physical, sexual or witnessed abuse
in childhood [26]. The PAG is intimately involved in defensive and anxiety-like behaviour [27]. Using functional neuroimaging the PAG was found to have decreased activation
when the subject was distracted from painful stimuli [28].
Given this link, we could therefore further hypothesise that
the combination of a dysfunctional PAG in EM with significant life-stressors could predispose to CDH.References1. (2004) The international classification of headache disorders, 2nd edn.
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Copyright Springer-Verlag 2004
Abstract
The objective was to provide objective imaging evidence of functional changes in brainstem structures involved in chronic daily headache (CDH). Over time, episodic migraine (EM) patients may develop CDH known as transformed migraine (TM). Using analysis of transverse relaxation rates, R2, R2* and R2 (R2* values are reflective of blood oxygen level dependence; R2 is a measure of non-heme iron in tissues) we have reported activation (hyperoxia) of red nucleus (RN) and substantia nigra (SN) (decreased R2* and R2) in CDH patients studied during headache, and dysfunction of periaqueductal grey (PAG) based on increased iron levels (elevated R2) [1]. We now report a patient with CDH who, upon treatment, reverted to EM, permitting studies when headache free and an objective analysis of treatment response. SP is a female aged 48 years. She presented with daily headaches for 6 months. Episodic headaches, meeting IHS criteria for migraine without aura, began in her 20s. At the time of presentation she was taking 5 tablets of ergotamine tartarate in the form of Ercaf and 6 extra-strength acetaminophen daily. Repeated dosages of intravenous dihydroergotamine for three days during withdrawal of all medications successfully achieved clinical reversion from CDH to EM. She was studied both during CDH and when headache free after reverting to EM, using high-resolution MR techniques to map the transverse relaxation rates R2, R2* and R2 in RN, SN and PAG. For technical reasons, PAG was not imaged during the CDH phase of her illness. During the CDH phase of her illness, respective R2* values were reduced compared to normal in the RN and SN to 30.1 m/s and 31.45 m/s. Similarly, R2 in RN and SN were abnormally low at 6.62 m/s and 6.72 m/s compared to normal. Subsequent headache free studies demonstrated that R2* and R2 in the RN became 40.1 m/s and 15.47 m/s respectively, and in the SN, 40.25 m/s and 15.19 m/s respectively. These values were similar to EM patients and normal controls. The R2 in PAG during EM for this subject was increased at 6.88 m/s but elevated compared to controls. Daily headache in this patient was associated with chronic activation of pain networks that included RN and SN. Resolution of headache was associated with resolution of activation, although there was evidence for persistent PAG dysfunction, as previously reported. To the best of our knowledge, this case represents the first objective correlation of functional changes in brainstem nociceptive networks with clinical features of TM and its response to treatment. [PUBLICATION ABSTRACT]
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer