Pathophysiology of Headache
Margarita Sánchez del Río, MD, and Uwe Reuter, MD
Address
Neurology Department, Hospital Ruber Internacional, Madrid, Spain.
E-mail: msanchezdelrio@hotmail.com
Current Neurology and Neuroscience Reports 2003, 3:109–114
Current Science Inc. ISSN 1528–4042
Copyright © 2003 by Current Science Inc.
Clinical features of different headache syndromes have been
described in great detail; however, its pathophysiology
remains poorly understood. We review the latest findings
in both human imaging studies and experimental animals to
explain the possible mechanisms involved in the genesis of
headache syndromes.
Introduction
Headaches are complex disorders characterized by
repeated attacks of headache and combinations of neuro-
logic, gastrointestinal, and autonomic symptoms.
Although typical and pure syndromes exist, there are many
transitional forms, and even the headaches of the same
individual may change with time or more than one type
may coexist. The scarcity of knowledge in the underlying
pathophysiology has made extremely difficult the task of
knowing whether we are facing the same disorder with dif-
ferent phenotypes or separate entities. Different theories
have tried to explain the pathophysiology of headaches,
but so far have not explained the whole spectrum of clini-
cal features. Herein we describe the mechanisms involved
in headache syndromes, focusing on selected topics related
to migraine aura and pain such as sensitization of trigemi-
nal neurons, nitric oxide, and new imaging data.
Aura
Transient focal neurologic symptoms occur in up to 31% of
migraine patients on some occasions and in approximately
14% in cluster headache patients [1•,2]. Even aura symp-
toms have been described in some cases of hemicrania
continua [3]. Although in 1958 Milner [4] was the first to
suggest a relationship between cortical spreading depres-
sion and migraine aura, it was not until recently that this
relationship was clearly proven [5•,6•]. Cortical spreading
depression is a wave of neuronal and glial depolarization
that marches across the cortex at a rate of 2 to 5 mm per
minute. Together with the depolarization, there is an
intense metabolic activity with release of potassium,
hydrogen ions, neurotransmitters, and metabolites such as
nitric oxide, adenosine, and arachidonic acid into the
extracellular and perivascular space. Within the perivascu-
lar space, these substances activate or sensitize perivascular
trigeminal fibers and transmit impulses centrally.
The initial groundbreaking work using xenon blood
flow studies was done by Olesen [7]. Subsequent func-
tional imaging studies have both corroborated the previ-
ous findings and further elucidated the underlying
mechanisms of migraine aura. Today we know that
migraine aura is characterized by a short phase of hyper-
emia that is likely to be the correlate of the flashing,
jagged lights described during the visual hallucinations
[5•]. Hyperemia is then followed by a wave of hypoper-
fusion that crosses vascular boundaries of contiguous
cortex at a rate of 3.5 ± 1.1 mm per minute [8]. Whereas
hyperemia is the response to increased neuronal activa-
tion, hypoperfusion reflects depressed neuronal function
and is still clearly present when the headache starts (Fig.
1). These findings, together with direct evidence that the
local oxygen supply is more than adequate and the pres-
ence of direct current shifts measured with magnetoen-
cephalography (MEG), support the concept of migraine
as a primarily neuronal disorder, whereas vascular
changes represent an epiphenomenona [6•,9,10].
Cortical hyperexcitability
It is unclear what triggers cortical events, but it is increas-
ingly evident that there seem to be factors that modify neu-
ronal excitability, especially in the occipital cortex,
reducing the threshold for cortical activation. This abnor-
mal responsiveness of the visual cortex is now a widely
appreciated characteristic of the migrainous brain, mani-
fested as an increased sensitivity to various physiologic
environmental stimuli such as lower thresholds of "low-
level visual" processing in the primary visual cortex and
deficient habituation [11,12]. Although the striate cortex
contains only 3% of the cerebral surface, approximately
10% of cortical neurons are said to be in it. This dense
packing of neurons may hypothetically contribute to the
abnormal excitability of the occipital cortex. Decreased
brain gamma-aminobutyric acid (GABA) levels may also
contribute to the lack of inhibitory control in visual cortex.
Antiepileptic drugs, which have proven efficacy in head-
ache prevention, are capable of decreasing cortical excit-
ability through the increase of brain GABA levels [13].
Genetic factors that lead to calcium channelopa-
thies (familial hemiplegic migraine), cell-surface recep-
tor dysfunction (cerebral autosomal dominant
110 Headache
Figure 1. Imaging the migraine aura with magnetic resonance imag-
ing (MRI). A, Time-dependent blood oxygenation level dependent
(BOLD) activity changes in the occipital cortex before and during
migraine visual aura. B, The MRI signal perturbation over time. Prior
to the onset of the aura, the BOLD response to visual stimulation
shows a normal, oscillating activation pattern. Following the onset of
aura (arrow), the BOLD response showed a marked increase in mean
level and a marked suppression to light modulation (hyperemia) fol-
lowed by a partial recovery of the response to light modulation at
decreased mean level (hypoperfusion). C, Pefusion weighted imaging
map obtained at approximately 70 minutes after the onset of a stereo-
typical visual aura and after resolution of the aura and into the head-
ache phase. A perfusion defect (decreased regional cerebral blood
flow [rCBF] and regional cerebral blood volume [latter not shown], or
increased mean transit time [MTT]) was observed in the occipital cor-
tex contralateral to the visual field defect.
arteriopathy with subcortical infarcts and leukoen-
cephalopathy [CADASIL]), or mitochondrial energy
defects (mitochondrial encephalomyopathy, lactic aci-
dosis and stroke-like syndrome [MELAS]) may also
contribute to lower the threshold for neuronal excita-
tion. Other factors, such as mitochondrial energy
impairment as seen in the MELAS, and even in
migraine with and without aura, alone or in combina-
tion with magnesium deficiency and environmental
factors such as stress and ovarian steroid, may also play
a relevant role in cortical excitability.
Pain
Migraine pain is mediated by the trigeminal nerve, and
numerous reports deal with the role of neuropeptides and
trigeminal-mediated meningeal and brainstem events [14].
The trigeminal nerve innervates blood vessels within ipsi-
lateral dura mater with pain sensitive c-fibers and A-δ
fibers, thereby creating one of the few pain-sensitive intra-
cranial structures. The cell bodies of primary trigeminal
neurons are located within the ipsilateral trigeminal gan-
glion. Once activated, the signal is transferred to secondary
neurons within the trigeminal brain's stem complex and
then transmitted to higher order neurons in the thalamus
and sensory cortex.
Sensitization
Sensitization, the painful perception of otherwise non-
noxi ous s t i mul i , oc c ur s i n as many as 80% of
migrai neurs during att acks and i s also seen in
migraineurs interictally [15]. The pain during migraine
is typically referred to the ipsilateral side of the head,
corresponding to the anatomic extension of the trigemi-
nal nerve. Coughing and head bending is perceived as
painful during migraine attacks, potentially due to
increased sensitivity of trigeminal ganglion neurons or
c-fibers within meninges. Sensitization spreads along
the trigeminal pain pathway centrally, resulting in
enhanced sensitivity of the ipsilateral facial skin, which
is innervated by the second and third branches of the
trigeminal nerve. When neuronal excitation affects
higher order neurons that receive convergent input from
the head and extracephalic tissue (eg, forearm skin), sen-
sitization also spreads clinically to the corresponding
sensory representation fields. This phenomenon devel-
ops gradually over several hours during migraine
attacks, which is consistent with the stepwise recruit-
ment of trigeminal and higher order neurons [16•].
These clinical observations are based on experimental
animal studies [17]. In these studies, chemically
induced meningeal inflammation in rats resulted in a
series of changes within primary (ganglion) and second-
ary (brainstem) trigeminal neurons: spontaneous neu-
ronal firing increases while the stimulus is applied to
the dura (20 minutes). More interestingly, the threshold
to meningeal mechanical indentation decreases and
mechanosensitivity of neurons to brush and pressure
applied to the facial skin increases slowly over time. In
parallel, heat sensitivity of trigeminal neurons also
increases and the dural receptive fields of the corre-
sponding neurons expand. Neuronal excitation and sen-
sitization reaches a maximum 2 to 4 hours after
experimental inflammation of the dura, with a gradual
recovery consistent with the findings in most humans
[18]. All these changes indicate gradually expanding
neuronal activation within the central trigeminal pain
network, because local anesthesia applied to the dura
does not abolish sensitization.
However, in a subgroup of migraineurs, trigeminal and
other pain-sensitive neurons appear to change their prop-
erties permanently. These patients show interictally
increased muscle tenderness of cervical muscles [19] or
reduced excitation for trigeminally mediated reflexes, in
particular on the side where migraine headache usually
occurs, indicative of permanent reduced threshold for neu-
rons involved in head pain generation [20]. The detailed
genetic, molecular, and biochemical mechanisms underly-
ing transient and permanent sensitization remain to be
determined. The candidates for both types of sensitization
could be proinflammatory mediators such as nitric oxide
synthase type II or cyclooxygenase-2, as demonstrated in
models of peripheral inflammatory pain [21].