Nouchine Hadjikhani, Margarita Sanchez del Rio, Ona Wu, Denis
Schwartz, Dick Bakker, Bruce Fischl, Kenneth K. Kwong, F. Michael Cutrer, Bruce
R. Rosen, Roger B. H. Tootell, A. Gregory Sorensen, and Michael A. Moskowitz
of migraine aura revealed by functional MRI in human visual cortex
PNAS 98: 4687-4692; published online before print as 10.1073/pnas.071582498
spreading depression (CSD) has been suggested to underlie migraine visual aura.
However, it has been challenging to test this hypothesis in human cerebral cortex.
Using high-field functional MRI with near-continuous recording during visual aura
in three subjects, we observed blood oxygenation level-dependent (BOLD) signal
changes that demonstrated at least eight characteristics of CSD, time-locked to
percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly
reflecting vasodilation), developed within extrastriate cortex (area V3A). This
BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital
cortex, congruent with the retinotopy of the visual percept. Following the same
retinotopic progression, the BOLD signal then diminished (possibly reflecting
vasoconstriction after the initial vasodilation), as did the BOLD response to
visual activation. During periods with no visual stimulation, but while the subject
was experiencing scintillations, BOLD signal followed the retinotopic progression
of the visual percept. These data strongly suggest that an electrophysiological
event such as CSD generates the aura in human visual cortex." [Full
of the migraine aura. The spreading depression theory.
1994 Feb;117 ( Pt 1):199-210.
"The characteristic form and development
of sensory disturbances during migraine auras suggests that the underlying mechanism
is a disturbance of the cerebral cortex, probably the cortical spreading depression
(CSD) of Leao. The demonstration of unique changes of brain blood flow during
attacks of migraine with aura, which have been replicated in animal experiments
during CSD, constitutes another important line of support for the 'spreading depression'
theory, which may be a key to an understanding of the migraine attack. Cortical
spreading depression is a short-lasting depolarization wave that moves across
the cortex at a rate of 3-5 mm/min. A brief phase of excitation heralds the reaction
which is immediately followed by prolonged nerve cell depression synchronously
with a dramatic failure of brain ion homeostasis, efflux of excitatory amino acids
from nerve cells and enhanced energy metabolism. Recent experimental work has
shown that CSD in the neocortex of a variety of species including man is dependent
on activation of a single receptor, the N-methyl-D-aspartate receptor, one of
the three subtypes of glutamate receptors. The combined experimental and clinical
studies point to fruitful areas in which to look for migraine treatments of the
future and provide a framework within which important aspects of the migraine
attack can be modelled." [Abstract]
A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner
A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ.
in human neocortical slices.
Brain Res. 2001 Jul 6;906(1-2):74-83.
spreading depression (CSD) occurrence has been suggested to be associated with
seizures, migraine aura, head injury and brain ischemia-infarction. Only few studies
identified CSD in human neocortical slices and no comprehensive study so far evaluated
this phenomenon in human. Using the neocortical tissue excised for treatment of
intractable epilepsy, we aimed to investigate CSD in human. CSD was induced by
KCl injection and by modulating T-type Ca(2+) currents in incubated human neocortical
tissues in an interphase mode. The DC-fluctuations were recorded by inserting
microelectrodes into different cortical layers. Local injection of KCl triggered
single CSD that propagated at 3.1+/-0.1 mm/min. Repetitive CSD also occurred spontaneously
during long lasting application (5 h) of the T-type Ca(2+) channel blockers amiloride
(50 microM) or NiCl(2) (10 microM) which was concomitant with a reversible extracellular
potassium increase up to 50 mM. CSD could be blocked by the N-methyl-D-aspartate
receptor antagonist 2-amino-5-phosphonovaleric acid in all cases. The results
demonstrate that modulation of the Ca(2+) dynamics conditioned human neocortical
slices and increased their susceptibility to generate CSD. Furthermore, these
data indicate that glutamatergic pathway plays a role in CSD phenomenon in human."
LC, Mody I
Protective Effect of Ifenprodil against Spreading Depression
in the Mouse Entorhinal Cortex.
J Neurophysiol. 2004 Jun
In the brain, spreading depression (SD) is characterized by a large extracellular
DC shift, a massive failure of ion homeostasis and a transient cessation of neuronal
function. Clinically, SD is believed to be involved in various neurological disorders
including migraine and cerebrovascular diseases. The propagation of cortical SD
requires the release of glutamate, and NMDA receptors play a crucial role in this
process. Here, we have isolated the NMDA-receptor-mediated component of extracellularly
recorded field EPSPs (fEPSPs) in layers 2-3 of the entorhinal cortex of murine
brain slices. In the absence of GABAA and AMPA receptor mediated synaptic transmission,
stimulation of layer 6 afferents every 15 - 90 s elicited spontaneous SD on average
within 18.5 min after the start of the stimulation. In the presence of ifenprodil,
an NR2B receptor subunit-selective NMDA receptor antagonist, the occurrence of
SD was nearly abolished. Our results are consistent with an important role of
NR2B subunits in triggering SD in the entorhinal cortex. [Abstract]
Benz B, Grima G, Do KQ
homocysteic acid release from astrocytes: possible implication in glia-neuron
cells synthesise neuroactive substances and release them upon neurotransmitter
receptor activation. Homocysteic acid (HCA), an endogenous agonist for glutamatergic
N-methyl-D-aspartate (NMDA) receptors, is predominantly localised in glial cells.
We have previously demonstrated the release of HCA from mouse astrocytes in culture
following activation of beta-adrenergic receptors. Moreover, a release of HCA
has also been observed in vivo upon physiological stimulation of sensory afferents
in the thalamus. Here we report the glutamate-induced release of HCA from astrocytes.
The effect of glutamate was mediated by the activation of ionotropic (NMDA and
non-NMDA) as well as by metabotropic receptors. In addition, the release of HCA
was Ca(2+)- and Na(+)-dependent, and its mechanism involved the activation of
the Na+/Ca(2+)-exchanger. Furthermore, we provide evidence for the presence of
functional NMDA receptors on astrocytes, which are coupled to an intracellular
Ca2+ increase via stimulation of the Na+/Ca(2+)-exchanger. Our data thus favour
a participation of glial cells in excitatory neurotransmission and corroborate
the role of HCA as a "gliotransmitter." [Abstract]
Qi, Savage, Jason E., Hufeisen, Sandra J., Rauser, Laura, Grajkowska, Ewa, Ernsberger,
Paul, Wroblewski, Jarda T., Nadeau, Joseph H., Roth, Bryan L.
Sulfinic Acid and Other Acidic Homocysteine Derivatives Are Potent and Selective
Metabotropic Glutamate Receptor Agonists
J Pharmacol Exp
Ther 2003 305: 131-142
"... because homocysteine is also involved in normal
metabolic pathways of many biologically functional molecules, abnormalities in
homocysteine metabolism may adversely affect many related and unrelated pathways
which, in turn, cause diseases and disorders." [Full
Görtz P, Hoinkes A, Fleischer W, Otto F, Schwahn
B, Wendel U, Siebler M
Implications for hyperhomocysteinemia:
not homocysteine but its oxidized forms strongly inhibit neuronal network activity.
Neurol Sci. 2004 Mar 15;218(1-2):109-14.
Severe hyperhomocysteinemia (50-200
microM) often presents itself with acute neuronal dysfunction including seizures
and psychosis. Its moderate form (15-50 microM) is associated with cognitive impairment
and dementia. We investigated the neuropharmacological effects of homocysteine
and its oxidized forms, homocysteinesulfinic acid (HCSA) and homocysteic acid
(HCA), on neuronal network function utilizing dissociated cortical neurons from
embryonic Wistar rats on microelectrode arrays. All substances inhibited dose-dependently
and reversibly spontaneous neuronal network activity within seconds: L-HCSA and
L-HCA blocked spontaneous spike rate (SSR) significantly at very low concentrations,
with an IC50 of 1.9 and 1.3 microM, respectively; whereas the dose-response curve
of D,L-homocysteine revealed an IC50 of 401 microM. These effects were antagonized
by 2-amino-5-phosphonovaleric acid (APV) pointing to the NMDA receptor as mediator
of this fast and reversible inhibition of network activity. We conclude that a
neuronal dysfunction observed in hyperhomocysteinemia is likely due to HCSA and
HCA since effective concentrations of homocysteine are not reached in patients.
RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR
methylenetetrahydrofolate reductase gene variant C677T influences susceptibility
to migraine with aura.
BMC Med. 2004 Feb 12;2(1):3.
The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated
with increased levels of circulating homocysteine and is a mild risk factor for
vascular disease. Migraine, with and without aura (MA and MO), is a prevalent
and complex neurovascular disorder that may also be affected by genetically influenced
hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene
is associated with migraine susceptibility we utilised unrelated and family-based
case-control study designs. METHODS: A total of 652 Caucasian migraine cases were
investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated
migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex
pedigrees. RESULTS: In the unrelated case-control sample we observed an over-representation
of the 677T allele in migraine patients compared to controls, specifically for
the MA subtype (40% vs. 33%) (chi2 = 5.70, P = 0.017). The Armitage test for trend
indicated a significant dosage effect of the risk allele (T) for MA (chi2 = 5.72,
P = 0.017). This linear trend was also present in the independent family-based
sample (chi2 = 4.25, Padjusted = 0.039). Overall, our results indicate that the
T/T genotype confers a modest, yet significant, increase in risk for the MA subtype
(odds ratio: 2.0 - 2.5). No increased risk for the MO subtype was observed (P
> 0.05). CONCLUSIONS: In Caucasians, the C677T variant in the MTHFR gene
influences susceptibility to MA, but not MO. Investigation into the enzyme activity
of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.
A, Valle N, Bravo Y, Muńoz P, Sánchez-Velasco P, Ruiz-Alegría C, Castillo J, Leyva-Cobián
F, Vadillo A, Pascual J
MTHFR T677 homozygosis influences
the presence of aura in migraineurs.
It has been suggested that folate metabolism could be
involved in migraine pathogenesis. We analysed the 5',10'-methylenetetrahydrofolate
reductase (MTHFR) genotypic distribution in a large migraine sample. We genotyped
230 migraine patients (152 migraine without aura (MO) and 78 migraine with aura
(MA)) and 204 nonheadache controls. The incidence of TT homozygosis for migraine
in general (12%), MO (9%) and MA (18%) did not significantly differ from that
found in healthy controls (13%). Differences were significant when the frequency
of TT homozygosis between MA and MO (P = 0.03, OR = 2.34, 95% CI = 1.04-5.26)
was compared. There was a tendency for a higher frequency of the MTHFR T allele
in the MA group (42%) as compared to MO (29%) and controls (36%). These differences
were significant only in the case of MA vs. MO (P = 0.006, OR = 1.75, 95% CI =
1.15-2.65). These results could indicate that the MTHFR C677T polymorphism, causing
mild hyperhomocystinaemia, might be a genetic risk factor for experiencing aura
among migraineurs. Overall, however, there was no association between migraine
and the C677T MTHFR polymorphism. [Abstract]
I, Sazci A, Ergul E, Kaya G, Kilic G
the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase
gene in patients with migraine risk.
Brain Res Mol
Brain Res. 2003 Mar 17;111(1-2):84-90.
Although controversial, diminished activity
of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine
metabolism, may predispose to migraine in Turkish people. In a case-control study,
we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C,
in 102 migraine patients (23 migraine with aura, 70 migraine without aura and
nine with tension-type headache) and compared it to that of 136 healthy controls.
The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were
significantly higher in the total migraine population (33.82%, 33.82%) than in
controls (25.38% and 24.26%), respectively.The genotypes T677T and C1298C were
the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457;
P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals
with migraine with aura with C1298C and C677C/C1298C genotypes were even more
profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320;
P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However
individuals with migraine without aura with T677T and C1298C genotypes showed
the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with
C1298C and C677C/C1298C genotypes may also predispose to tension-type headache
(OR=8.375; 95% CI=0.685-102.458); P=0.049). [Abstract]
H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K
homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a
genetic risk factor for migraine.
Am J Med Genet.
2000 Dec 4;96(6):762-4.
Increased homocysteine levels are associated with various
pathological conditions in humans, including stroke and cardiovascular disorders.
Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold
of migraine headache. Frosst et al.  reported an association between the
homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR)
gene and serum homocysteine levels. This study was designed to determine the prevalence
of the MTHFR mutation in Japanese patients with migraine and tension-type headache
(TH). Seventy-four patients with migraine headaches (22 with aura and 52 without
aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR
C677T polymorphism was performed by polymerase chain reaction-restriction fragment
length polymorphism. We detected that the incidence of the homozygous transition
(T/T) in migraine sufferers (20.3%) was significantly higher than that in controls
(9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine
headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent
in the migraine group than in the control group. Our results support the conclusion
that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor
for migraine. [Abstract]
CR, Hassell KL, Deutsch JC, Kolhouse JF.
Are neuropsychiatric manifestations
of folate, cobalamin and pyridoxine deficiency mediated through imbalances in
excitatory sulfur amino acids?
Med Hypotheses. 1994 Oct;43(4):239-44.
cobalamin and pyridoxine deficiency are associated with psychiatric or neurological
symptomatology. Disturbances in sulfur amino acid metabolism leading to accumulation
of homocysteine occurs in all three conditions as the metabolism of homocysteine
depends on enzymes requiring these vitamins as cofactors. Oxidation products of
homocysteine (homocysteine sulfinic acid and homocysteic acid) and cysteine (cysteine
sulfinic acid and cysteic acid) are excitatory sulfur amino acids and may act
as excitatory neurotransmitters, whereas taurine and hypotaurine (decarboxylation
products of cysteic acid and cysteine sulfinic acid) may act as inhibitory transmitters.
Homocysteic acid and cysteine sulfinic acid have been considered as endogenous
ligands for the N-methyl-D-aspartate (NMDA) type of glutamate receptors. The profile
of these sulfur amino acid neurotransmitters could be altered in a similar fashion
in states of decreased availability of folate, cobalamin or pyridoxine. It is
proposed that the mechanism of neuropsychiatric manifestations in all three conditions
result from a combination of two insults to homocysteine catabolism in the brain.