Functional1H-MRS findings in migraine patients with and without
aura assessed interictally
Paola Sarchielli,a,*Roberto Tarducci,bOtello Presciutti,bGianni Gobbi,bGian Piero Pelliccioli,c
Giuseppe Stipa,aAndrea Alberti,aand Giuseppe Capocchia
aNeuroscience Department, University of Perugia, Policlinico Monteluce, Via E Dal Pozzo, 06126 Perugia, Italy
bInstitute of Medical Physics, Azienda Ospedaliera of Perugia, Italy
cInstitute of Neuroradiology, Azienda Ospedaliera of Perugia, Italy
Received 12 April 2004; revised 26 October 2004; accepted 3 November 2004
Available online 5 January 2005
The present study was aimed at investigating changes in brain
metabolites due to visual cortex activation in migraineurs and normal
subjects by1H-magnetic resonance spectroscopy (MRS). Twenty-two
migraine patients with aura, 22 migraine patients without aura, and 10
control subjects were assessed. The volume of interest (about 8 cm3)
was placed on the visual cortex area and the visual stimulus was
applied using MR-compatible goggles with a flashing red light at a
frequency of 8 Hz and an intensity of 14 lx. Data were acquired over
36V 40U. The experimental time course was: baseline phase, from 0 to
3V 40U (1 spectrum); on phase (flashing light condition), from 3V 40U to
29V 20U (1540U) (7 spectra), and off phase, from 29V 20U to the end of the
experiment at 36V 40U (2 spectra). The main result of photic stimulation
in patients with migraine with aura is the more consistent decrease
(?14.61%) of the N-acetylaspartate (NAA) signal, which is significantly
greater than that found in migraine patients without aura and control
subjects. A parallel slight increase in the lactate peak was also detected.
The above findings support little differences in brain metabolites
between the two patient groups assessed in interictal periods, which
suggests a less efficient mitochondrial functioning in migraine with
D 2004 Elsevier Inc. All rights reserved.
without aura; N-acetylaspartate; Lactate
1H-MRS; Photic stimulation; Migraine with aura; Migraine
In the last few years, several studies of magnetic resonance
spectroscopy (MRS), a non-invasive technique that allows the
investigation of variations in some cerebral metabolites, and in
31phosphorus (P)-MRS, demonstrated a metabolic
disturbance in the brain of migraine patients with aura (MwA)
and, to a lesser extent, of migraine patients without aura (MwoA),
which is evident even in the interictal period (Barbiroli et al.,
1992; Lodi et al., 1997a; Montagna et al., 1994a,b; Presedo,
1991; Sacquegna et al., 1992; Welch et al., 1989, 1993). Such
alterations concern energy metabolism and consist of increased
inorganic phosphorus and ADP, reduced phosphocreatine, and
decreased phosphorylation potential, which do not seem limited
to the brain but also involve the muscles. There was also a slow
post-exercise recovery rate of phosphocreatine levels in skeletal
muscle, which is entirely related to mitochondrial respiration, also
slow in the same patients (Barbiroli et al., 1992; Lodi et al.,
The reduced energy potential was interpreted as being
indicative of a reduced mitochondrial reservoir and was hypothe-
sized to be the biochemical substrate of the susceptibility to attacks
in migraineurs (Boska et al., 2002; Lodi et al., 2001).
The reduction in free magnesium observed in the brain of
migraine patients was also associated with mitochondrial dysfunc-
tion and therefore considered secondary to the impairment of
energy metabolism. Both reduction in ATP hydrolysis and low
brain cytosolic-free magnesium showed a trend paralleling the
severity of the clinical phenotype, with the highest values in
patients with migraine stroke and the lowest in MwoA patients
(Schoenen, 1996). In contrast, a recent study by Boska et al. (2002)
did not show consistent abnormalities of energy metabolism, but
rather supported a disturbance of magnesium ion metabolism,
which could contribute to brain cortical hyperexcitability, that is
more accentuated with increasing severity of neurologic symptoms
in MwA patients.
An increase in the mechanisms involved in obtaining an
efficient arousal is needed in the presence of a reduced energy
reservoir in the migraineur’s brain and this, together with the
derangement in monoaminergic pathways, could explain the
alteration found in the evoked (including the visual) and event-
related (such as the contingent negative variation) potentials. They
can be summarized as a dependence of the evoked or event-related
1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved.
* Corresponding author. Fax: +39 075 5783583.
E-mail addresses: firstname.lastname@example.org, email@example.com
Available online on ScienceDirect (www.sciencedirect.com).
NeuroImage 24 (2005) 1025–1031
response on the intensity of the suprathreshold stimuli, indicated as
a lack of habituation and potentiation of the response after repeated
stimuli (Boska et al., 2002; Gerber and Schoenen, 1998).
The visual cortex, due to the relatively low neuronal/glial cells
ratio, appears particularly susceptible to the metabolic shift
characterizing the alteration in cortical homeostatic mechanisms
in migraineurs. This metabolic shift may play a fundamental role in
the pathophysiology of migraine aura.
Elevated interictal levels of cerebral lactate were found in the
visual brain of a few migraine patients (Watanabe et al., 1994,
1996). This was particularly evident in migraine patients who had
experienced a migraine attack within the previous 2 months but not
in patients with a longer attack-free period (Watanabe et al., 1996).
These findings were interpreted as an expression of a derangement
of oxidative glycolysis in favor of anaerobic glycolysis, which
occurs even in the interictal period immediately before the attacks,
and which can be normalized by a long attack-free period.
No studies have been performed to verify the changes in brain
metabolites due to photic stimulation in patients affected by visual
aura. We therefore carried out a study using functional1H-MRS
with photic (flash) stimulation in MwA and MwoA patients
assessed at least 72 h from the last attack, and at least 48 h before
the following attack, comparing brain metabolite changes with
those in a group of age- and sex-matched control subjects.
Twenty-two patients affected by MwA, 22 patients suffering
from MwoA attending the Headache Center of the Neuroscience
Department of the University of Perugia, and 10 age- and sex-
matched control subjects (C) were admitted to the study. All
subjects participating in the study gave their informed consent.
Migraine diagnosis was made according to the International
Classification of Headache Disorders, 2nd ed. (2004).
The frequency and characteristics of attacks were recorded by a
headache diary in the last 3 months. The time from the last attack
was also registered.
The details of migraine patients and control subjects are given
in Table 1.
None of the patients took prophylactic drugs for their attacks.
They were all assessed interictally at least 72 h from the last attack.
Moreover, the recording of the attacks in the headache diaries made
it possible to verify that none of the MwA and MwoA patients
experienced a crisis within 48 h after the spectroscopic session.
All MwA patients experienced visual disturbances during the
aura phase consisting of positive and negative scotomas, flashes,
and fortification spectra. Eleven of them also reported sensory
disturbances in the same phase consisting of paresthesias in the
hand, arm, and/or perioral zone ipsilateral to the visual disturban-
ces in at least 80% of auras experienced. Motor deficit symptoms
were reported by 2 patients and dysphasic symptoms by one
patient. In none of the MwA patients was aura induced by visual
stimuli in the experimental setting.
In all patients with only visual aura symptoms, the duration was
less than 60 min (typical aura). Complex auras (visual plus motor
and/or sensory and dysphasic symptoms) were of longer duration
1H-MRS with photic stimulation
1H-MRS was carried out using a whole body scanner (GEMS
LX system) of 1.5 T with standard head coil. For spectroscopic
acquisition, the PRESS pulse sequences were used with: TE = 144
ms, TR = 2000 ms, average number = 64. Each acquisition lasted
220 s. The FID was elaborated as follows: phase artifacts
correction, baseline correction, Gaussian–Lorentzian filter in time
domain (4 Hz, 4 Hz), FFT and Marquard–Levenberg fit in
frequency domain. For each patient, the peak area (in arbitrary
units) and its percent variation with respect to its first value (OFF
status) of N-acetylaspartate (NAA), Creatine (Cr), and Choline
(Cho) were considered for statistical analysis. For each patient, we
directly compared the peak areas measured at different time points
during the same examination session. This was possible because
the acquisition conditions for each patient did not vary during the
same examination session and because tomograph functioning was
stable for the whole session, as previously verified with measures
carried out on a water phantom.
The volume of interest (VOI) was placed on the visual cortex,
centered on the calcarine sulcus, and included the primary and
secondary visual cortices (Brodmann’s areas 17, 18, 19).
With the aim of checking the exact location of the VOI,
preliminary fMRI studies were carried out on normal volunteers
(Fig. 1) using the same photic stimulation. The selected VOI
corresponded to the area of maximal activation on fMRI (Figs. 2a,
For fMRI, we used an EPI sequence (epibold, GE Medical
Systems) with TR/TE = 2s/40 ms, 10 slices/sequence (FOV = 24
cm, 128 ? 128 matrix, slice thickness = 5 mm) localized on the
occipital visual cortex. The acquisition protocol was: 20 s with no
photic stimulation (OFF state) and 20 s with photic stimulation
(ON state) repeated alternately eight times for a total of 1600
images. The images were realigned and elaborated with SPM99
Details of MwA and MwoA patients and control subjects (C)
Mean F 2SD
34.5 F 4.9
37.2 F 5.1
33.3 F 6.4
Aura symptoms in patients assessed with migraine with aura
Aura symptoms No. of patientsMean duration (min)
Visual + sensory
Visual + sensory + dysphasic
Maximum signal variation (difference from the basal value in percent) of
the cerebral metabolites NAA and Cr due to visual stimulation (on phase) in
the three groups examined
?7.42 F 2.63
?5.79 F 0.50
?14.05 F 4.0
?11.66 F 3.74
?11.71 F 6.81
?12.50 F 0.62
P. Sarchielli et al. / NeuroImage 24 (2005) 1025–1031
(http://www.fil.ion.ucl.ac.uk/spm) and the significance level
chosen was P b 0.05 (corrected for multiple comparison).
The visual stimulus was applied using MR-compatible goggles
with a flashing red light at a frequency = 8 Hz and an intensity = 14
l?. Data were acquired over 36V 40U. The experimental time course
was: baseline phase, from 0 to 3V 40U (1 spectrum); on phase
(flashing light condition), from 3V 40U to 29V 20U (1540U) (7 spectra),
and off phase, from 29V 20U to the end of the experiment at 36V 40U (2
The influence of blinking and opening the eyes on the results of
the functional spectroscopy was also verified, although it should be
noted that a light of 14 lx was quite easy to bear for the subjects.
For this purpose, a simple system (photoluxometer) was developed
to check if the eyes were kept open during visual stimulation,
based on the different light reflexivity properties of the eyeballs
and eyelids. This device was able to detect a difference of about 1
lx between the open and blinking eyelid (Fig. 3).
Data are shown as mean F 2SD. ANOVA with Least
Significant Difference (LSD) test was used to compare the mean
of NAA decrease (%). Avalue of P b 0.05 was chosen as the level
of minimum significance.
The short-term stability of the scanner was carefully analyzed to
avoid misinterpretation of the data. Using a phantom containing
NAA (20 mM), the maximum standard deviation of the NAA peak
area over 1 h of acquisition was equal to 2.3% of the initial value.
In normal subjects (three cases) with no stimulus, the maximum
standard deviation of the NAA peak area over 36V 40U was 4.3% of
the initial value. Moreover, the standard deviation of total Cr and
Fig. 1. fMRI carried out in healthy volunteers, using the same visual
stimulation of the functional spectroscopy, aimed at verifying the correct
positioning of the VOI.
Fig. 2. VOI selected for the spectroscopic acquisition over the calcarine sulcus based on the preliminary fMRI study (a: sagittal section, b: axial section).
Fig. 3. Variations in the light reflexivity (lx) measured with a photo-
luxometer when the eyes are closed (eyes closed) and the eyes are opened
P. Sarchielli et al. / NeuroImage 24 (2005) 1025–1031
Cho did not exceed 8% of the initial value. Fig. 4 shows the typical
time course of NAA variation.
A significant difference in NAA decrease compared with the
initial value (off phase) emerged between MwA and the other two
groups (P b 0.02), but no significant difference was found between
MwoA and controls (Table 3).
The percent variation for the same metabolite did not differ
between MwA patients with only visual aura symptoms and those
with more complex aura.
The Cr and Cho signals did not show any difference at baseline
between control and patient groups or any variation in all groups
examined during the entire photic stimulation.
To confirm the involvement of NAA in MwA pathophysiology,
we also calculated the NAA/Cho ratio at baseline before photic
stimulation. We found a significant difference in this ratio between
MwA and the other two groups (P b 0.01), but no significant
difference between MwoA and control subjects (Fig. 5). A similar
difference was found for the NAA/Cr ratio (P b 0.02), whereas no
variations emerged for the Cho/Cr ratio between all groups. The
changes both in NAA/Cho and NAA/Cr ratios but not between
Cho/Cr between patient groups support the real decrease of NAA
rather than the large variability of both metabolites in the former
The stimulus phase of 1760 s induced only a small amount of
lactate in our spectra, roughly estimated to be less than 0.45 mM.
An example of the lactate peak detected as a consequence of photic
stimulation is displayed in Fig. 6. The spectrum shown is the result
of the summation of the 2nd and 3rd spectra acquired in the on
phase because the other spectra did not further contribute to the
lactate signal. Since the PRESS and TE= 144 ms were used, the
lactate signal, located between 1.4 and 1.3 ppm, was in phase
inversion compared with the other peaks.
Functional MRS is a technique that makes it possible to
measure metabolic changes in terms of MR spectroscopy-
detectable metabolites during neuronal activation (Richards et al.,
1998). This may be a more direct measurement of cellular events
occurring during neuronal activation than functional magnetic
resonance imaging. We used this technique to assess metabolic
changes in migraineurs with and without aura in the interictal
period due to photic stimulation.
The most remarkable result of the present functional1H-MRS
study is the more consistent decrease (?14.61%) in the NAA
signal in MwA patients compared with MwoA patients and control
individuals. The NAA decline after photic stimulation is followed
by a progressive recovery that is greater in MwoA patients and
A slight increase in the lactate peak was also found, which was
greater in MwA than in MwoA patients and controls. This increase
occurred in the first minutes of photic stimulation, then declined in
the following minutes of flash stimulation.
N-acetylaspartate is considered a marker of neuronal, and in
particular, axonal integrity, and because it is synthesized and
located prevalently in neural mitochondria, where it seems to be
Fig. 4. Typical NAA signal variation (%) in MwA patients, MwoA patients, and control subjects due to photic stimulation.
Fig. 5. Scatter plot of NAA/Cho ratios calculated in baseline phase for
Controls, MwA, and MwoA patients.
P. Sarchielli et al. / NeuroImage 24 (2005) 1025–1031
involved in mitochondrial/cytosolic carbon transport, it has been
taken as a marker of mitochondrial functioning (Clark, 1998; Patel
and Clark, 1979).
The importance of the mitochondrial energy state in the
synthesis of NAA was emphasized by Bates et al. (1996) in
research carried out on isolated brain mitochondria, suggesting that
NAA loss might result from a decrease in NAA formation
subsequent to ATP depletion. This dependency of NAA on energy
metabolism and the relationship between the NAA signal and
mitochondrial function was confirmed by other experimental
findings (Heales et al., 1995; Signoretti et al., 2001).
The role of NAA as a marker, not only of irreversible neural
loss but also of mitochondrial dysfunction, is further supported by
the recovery of its signal resonance in several pathological
conditions, such as multiple sclerosis, traumatic injury, stroke,
and also mitochondrial encephalopathy with lactic acidosis and
stroke-like syndrome (MELAS) (De Stefano et al., 1995; Houkin et
al., 1993; Kamada et al., 2001). The metabolic recovery was in
some cases associated with functional recovery from neurological
impairment (De Stefano et al., 1993; Garnett et al., 2001; Kamada
et al., 1997; Narayanan et al., 2001).
In MwA patients, a derangement of resting energy metabolism
has been clearly demonstrated. This is believed to contribute to
defining the pathophysiological substrate underlying migraine aura.
Our finding of a greater decrease in NAA at baseline (before
visual stimulation) in MwA patients lets us hypothesize a less
efficient mitochondrial functioning in MwA patients compared
with MwoA patients.
The basic physiological principle for functional brain imaging
is represented by the tight coupling between neuronal activity and
the associated increase in local blood flow and energy metabolism
(Aubert and Costalat, 2002).
Few studies have been carried out by
changes in the neural response in terms of variations in cerebral
1H-MRS to assess
metabolite peaks related to an increased metabolic demand during
activation, both in healthy and pathological conditions.
Analyzing the time course of NAA in the occipital lobes, we
found a decrease of this metabolite during photic stimulation which
occurred both in controls and migraine patients. This was more
consistent in MwA patients compared with MwoA patients and
Recent evidence suggests an intercompartmental cycle for NAA
and N-acetylaspartylglutamate (NAAG) (which contribute to the
1H-MRS NAA signal), in which they are released by neurons in a
regulated fashion and then hydrolyzed by catabolic enzymes
associated with glial cells. Recently, the catabolic enzyme for NAA
hydrolysis has been found to be expressed only in oligodendro-
cytes and that of NAAG hydrolysis only in astrocytes. The end-
products of NAA hydrolysis, acetate and aspartate, may serve as
return signalling to neurons for resynthesis. This unique metabolic
compartmentalization suggests a key role for both NAA and
NAAG in neuronal–glial cell-specific signalling and communica-
tion, which may participate in the control of many functions and
structures of the brain (Baslow, 2000).
The reversible loss of NAA found in our study cannot be
attributed, however, to a rapid degradation in the glial compartment
of NAA and NAAG and a subsequent rapid resynthesis of NAA in
neurons. This is difficult to accept as a possible explanation
considering its very slow metabolic rate demonstrated by
uptake studies and1H-MRS post-mortem spectroscopy in rats.
The redistribution of NAA from intra- to extracellular space
could account for rapid changes in NAA signals due to variation in
its chemical environment that may alter its magnetic resonance
visibility (Taylor et al., 1995).
The mechanisms of NAA release from neurons are unknown
but may involve the activation of specific channels/carriers—
possibly in relation to a volume regulatory response, which can
result in rapid changes in the NAA signal.
Fig. 6. Spectrum obtained in MwA patients as the sum of the 2nd + 3rd ON phase spectra; a small peak corresponding to lactate (1.33 ppm) is evident.
P. Sarchielli et al. / NeuroImage 24 (2005) 1025–1031
The latter can also be related to changes of the water
diffusion coefficient, which have been observed in human
occipital cortex during visual stimulation, taking into consider-
ation the osmoregulatory role of NAA (Baslow and Guilfoyle,
2002; Darquie et al., 2001).
The more rapid changes in and lower recovery of NAA in the
visual cortex in MwA patients may suggest a less efficient adaptive
decrease in neuronal activity than in MwoA patients, as a
consequence of repeated visual stimulation.
Whether a less efficient mitochondrial functioning in MwA
patients can be hypothesized on the basis of the greater decrease in
NAA compared to MwoA patients, the difference between the two
patient groups, evaluated in the interictal period, is not as great, as
emerged from the difference in variations of NAA intensities of
about 7% (expressed in arbitrary units) between the two patient
These data, both in controls and migraine patients, should also
be evaluated in light of the BOLD effects on cerebral metabolite
resonances in human visual cortex during visual stimulation using
1H-MRS (Zhu and Chen, 2001).
The slight rise in lactate observed in our study during photic
stimulation is not as considerable as that found in previous research
compared with the values measured in the off phase (Chen et al.,
et al., 1992).
The discrepancy between our results and those of the above
studies can be attributed, not only to the different methodological
approach and the different stimulus applied (flash vs. checkerboard)
but also to the use of the lactate/NAA ratio in some studies, which
could give an over-estimation of lactate, especially if changes in
NAA concomitantly occur (Sappey-Marinier et al., 1992).
The results of research performed with1H-MRS in animals do
not show significant changes in the lactate peak due to visual
stimulation and therefore suggest that increased brain electrical
activity is accompanied by increased cerebral energy consumption
in the involved areas, with a close stoichiometric coupling
between glucose utilization and oxidative metabolism (Kauppinen
et al., 1997).
In contrast, the small and transient increase in lactate observed
by us at the beginning of photic stimulation in our control subjects
and MwoA patients, and to a greater extent in MwA patients,
concurs with MRS findings in humans, which suggest a transient
dynamic uncoupling following a rapid recoupling of oxidative
metabolism after stimulation (Frahm et al., 1996).
In both our controls and migraine patients, especially those with
aura, we can postulate that if a transient excess of oxidative
glycolysis occurs, it represents a minor transitory component. The
metabolic mismatching during increased energy consumption is
minimal and only small variations of lactate can be detected by1H-
MRS. This hypothesis is consistent with results of studies at the
cellular level that indicate an initial glycolytic processing of
glucose occurring in astroglial cells during activation, resulting in a
transient lactate overproduction followed by a recoupling phase,
during which lactate seems to be oxidized by neurons (Magistretti
and Pellerin, 1999).
Further studies should be carried out to confirm our findings in
larger patient groups with the aim of verifying the extent of MRS
metabolite variations in relation to migraine severity. Patients with
different attack frequencies and different inter-attack intervals
should also be assessed. The paper by Watanabe et al. (1994)
should be mentioned in this regard. The authors found high levels
of lactate in 5 of 6 MwA patients who had experienced a migraine
attack within the previous 2 months, but not in a patient who had
not experienced a migraine attack in the previous 4 years. These
results were interpreted as indicating a reversible brain impairment.
According to the authors, a long attack-free period could, in fact,
normalize the subclinical disturbances.
Considering the above results, it cannot be excluded that lactate
may accumulate to a greater extent during migraine attacks when
more relevant metabolic changes occur, which contribute to
precipitate and maintain migraine with aura attacks. This aspect
should be investigated in future research.
Regarding the methodological approach, further studies are
needed to investigate brain metabolic changes due to different
photic stimuli (different stimulus intensities and different types of
stimuli—flash or checkerboard). In the few MwA patients to whom
we applied both stimuli (unpublished data), we found a more
significant decrease of NAA, but no significant differences were
found in the small increase in the lactate signal when the two types
of stimulation were used. These findings should, therefore, be
reconfirmed in control subjects and in large MwA and MwoA
At least two dark/light paradigms should be used to assess
habituation, which is impaired in migraine patients. Finally, the
potential visual response using the same stimuli and interpreted
considering SPECT and PET findings, to elucidate the relationship
between brain metabolite changes detected by1H-MRS and the
variations in cerebral blood flow in migraine, particularly with aura.
1H-MRS should be correlated with the evoked
The authors express their gratitude to John A. Toomey for
editing the English and Marisa M. Morson for technical assistance.
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