Headaches are estimated to affect more than 90% of the general population at some point in their lives¹ and may be encountered by physicians in a wide variety of clinical settings. Headaches can be divided into two major categories. The overwhelming majority of recurrent headaches are primary headache disorders, in which no identifiable underlying cause can be found. Secondary headache disorders are symptomatic of an underlying pathological cause. Secondary headaches can be due to causes such as transient viral illness, intracranial tumor, aneurysm, or drug withdrawal (for differential diagnosis of secondary headache disorder, see Cutrer²). Prevalence studies indicate that a benign process, such as a mild febrile illness or alcohol withdrawal, usually causes secondary headaches and that the lifetime prevalence of headache resulting from more ominous intracranial structural lesions is less than 2%.³

Head pain occurs when nociceptive neurons within the trigeminal, vagus, or glossopharyngeal cranial nerves or within the upper cervical roots become depolarized. Information from procedures involving intracerebral electrode implantation suggests that direct electrical or mechanical activation of areas within the brain involved in pain processing may also cause head pain.⁴ The causes of head pain vary widely and include not only direct mechanical, chemical, or inflammatory stimulation of pain-generating structures but also less well-characterized events that occur in primary headache disorders. After being initiated, the transmission and processing of the painful information is likely to be quite similar regardless of the inciting cause. This chapter reviews the anatomy involved in generating generic head pain and then discusses current theories of the pathophysiology of the major primary headache disorders, including migraine, cluster headache, and tension-type headache (TTH).

Under normal physiologic conditions, the brain is largely insensate. This has been demonstrated in neurosurgical procedures in which stimulation of the brain parenchyma in awake patients caused no pain.^5,6 Head pain is mediated by projections from the trigeminal and upper cervical dorsal root ganglia, which innervate the pial, dural, and extracranial blood vessels. In general, these pseudounipolar neurons innervate the vessels on the same side, which can explain the unilateral distribution of pain in certain headache types, but some of the cells project bilaterally to innervate midline vessels. On activation, these unmyelinated C fibers transmit nociceptive information from perivascular terminals through the trigeminal ganglia⁷ to project centrally to synapses on second-order neurons within the trigeminal nucleus caudalis. The primary neurotransmitter for the C fibers is glutamate, but the primary afferents also co-store substance P, calcitonin gene–related peptide (CGRP), and neurokinin A, as well as other neurotransmitters and neuromodulators, in their central and peripheral (e.g., meningeal) axons.

Activity in the trigeminal nucleus caudalis can be modulated by projections from rostral trigeminal nuclei,⁸ the periaqueductal gray matter, and the nucleus raphe magnus,⁹ as well as by descending cortical inhibitory systems.^9,10 From the trigeminal nucleus caudalis, second-order neurons transmit the nociceptive information, projecting to numerous subcortical sites, including the more rostral portions of the trigeminal complex,¹¹ the reticular formation of the brainstem,¹² midbrain and pontine parabrachial nuclei,^13,14 and the cerebellum,^15,16 as well as to the ventrobasal thalamus,^11,16–18 the posterior thalamus,^19,20 and the medial thalamus.²¹ From the rostral brainstem, nociceptive information is transmitted to other areas of the brain (e.g., limbic areas) involved in the emotional and vegetative responses to pain.¹³ From the ventrobasal thalamus, projections are sent to the somatosensory cortex, where discrimination and localization of pain are thought to occur. The medial thalamus projects to frontal cortex, where the affective and motivational responses to pain are thought to be mediated. In addition, evidence from positron emission tomography (PET) studies indicates that the medial thalamus may participate in the transmission of both discriminative and affective components of pain.²²

Migraine is one of the most common primary headache disorders and is characterized by throbbing headaches associated with nausea, vomiting, photophobia, and phonophobia. Before the onset or during the early phase of a headache, some individuals with migraine experience transient focal neurologic symptoms, which may include visual disturbances, unilateral numbness, unilateral weakness, and language dysfunction. These neurologic symptoms are collectively known as migraine aura. At the most basic level, migraine for most people is a complex genetic disorder with susceptibility arising from one or more variants in their genetic code. The details of how the susceptibility activates the migraine attacks are still incompletely understood. Because of the neurologic symptoms of migraine aura, the prevalence of migraine, and the intensity the headache, the research and speculation surrounding the pathophysiology of migraine has been the most intensive of all primary headache disorders. The speculation that has arisen around migraine has greatly influenced the discussion of pathophysiology of other headache syndromes. Traditional theories of migraine pathogenesis fall into two categories, vasogenic and neurogenic.

VASOGENIC THEORY

In the late 1930s, Dr. Harold Wolff²³ and coworkers observed that (1) extracranial vessels became distended and pulsated during migraine attacks in many patients, implying that dilation of cranial vessels might be important in migraine; (2) stimulation of intracranial vessels in awake patients resulted in an ipsilateral headache; and (3) vasoconstricting substances, such as ergotamine, could abort headaches, and vasodilatory substances, such as nitrates, could trigger migraine attacks. Based on these observations, it was theorized that intracranial vasoconstriction was responsible for the aura of migraine and that the subsequent headache resulted from a rebound dilation and distention of cranial vessels and activation of inflamed perivascular sensory neurons.

NEUROGENIC THEORY

The competing neurogenic theory held that migraine is a brain disorder based on an altered cerebral susceptibility to migraine attacks and that the vascular changes occurring during a migraine were the result rather than the cause of the attack. Advocates of the neurogenic theory pointed to the neurologic symptoms, both focal (in the aura) and vegetative (in the prodrome), that are often prominent components of migraine attacks, which cannot be explained on the basis of vasoconstriction within a single neurovascular territory. The expanding nature of the visual and sensory symptoms during migraine aura has led to speculation that the phenomenon of spreading depression might underlie the aura.²⁴ Spreading depression is a wave of neuronal hyperexcitation followed by suppression that is observed to move across areas of contiguous cortex in experimental animals after chemical or mechanical perturbation.²⁵ The speculation that spreading depression might be important in migraine aura was reawakened when Olesen, Lauritizen, and their colleagues used intraarterial xenon 133 (¹³³Xe) blood flow techniques to investigate the hemodynamic changes occurring during aura-like symptoms induced during carotid angiography. Olesen and coworkers reported that aura symptoms were accompanied by reductions in cerebral blood flow, usually in posterior regions of the brain.^26,27 Some studies reported a transient increase in blood flow before the blood flow reductions as well as an apparent anterior spread of the blood flow decrements, which moved across neurovascular boundaries.²⁷ The estimated rate of the spread was about 2 to 3 mm/min,²⁷ although the accuracy of this rate has been questioned because of the convoluted nature of the human cerebral cortex. The estimated reductions in blood flow observed in these ¹³³Xe blood flow studies ranged from 17%²⁸ to 35%,²⁶ which is well above the threshold (i.e., >75%) for frank ischemia and were therefore termed spreading oligemia. However, some researchers have speculated that the artifact of Compton scattering might account for both an underestimation of the magnitude of blood flow reduction and the apparent spreading pattern of the blood flow change.²⁹

If applied rigidly, neither of these traditional theories completely explains the clinical symptomatology of migraine. It is likely that migraine is not a disease per se but rather a syndrome in which acute attacks occur when one or more triggering environmental events interact with a vulnerable nervous system. The reasons why certain individuals possess this vulnerability to migraine attacks are not fully understood but are likely a result of a combination of genetic and acquired factors. There is great variability among the environmental triggers that are potentially capable of inciting a migraine attack. Most individuals with migraine are aware of several to which they are sensitive. The triggers most commonly reported include exposure to certain foods or food additives, certain types of physical exertion, alteration of usual sleep patterns, increased personal or professional stress, hormonal fluctuation, unaccustomed fasting, exposure to glaring or flickering lights, strong smells, and changes in weather patterns or barometric pressure. The triggers for attacks vary widely from one individual to another, and may change with time for an individual person with migraine. The mechanisms by which these provocative factors initiate a migraine are not well understood. Neither the biochemical nature nor the exact site of migraine initiation is known, but recent advances in functional neuroimaging are beginning to yield some clues.

Initiation

One study performed during the first 6 hours of nine spontaneous attacks of migraine without aura using PET has led to speculation that a so-called migraine generator may exist in the proximal brainstem.³⁰ In this study, a significant increase in regional cerebral blood flow (rCBF) was observed in the anterocaudal cingulate cortex, as well as the visual and auditory associative cortices. In addition, an 11% increase in rCBF was noted in medial brainstem structures over several planes slightly contralateral to the headache side. Activation in the medial brainstem but not the cingulate and auditory association cortices persisted even after effective treatment of the headache with 6 mg of subcutaneous sumatriptan. Activation within the medial brainstem was not observed during a subsequent study during a headache-free interval nor was it observed in another series after subcutaneous injection of capsaicin in the forehead.³¹ Although this pattern of activation in the brainstem takes place in a region important in nociceptive and vascular control (locus ceruleus and dorsal raphe nucleus), the persistence of the increase in rCBF after relief of symptoms has been interpreted to suggest the presence of a migraine generator. In contrast, other information based on molecular genetic investigations of familial hemiplegic migraine has suggested that altered activation thresholds within cortical neurons may be important in the initiation of migraine attacks in some patients.³²

Aura

Approximately 25% of individuals with migraine experience attacks in which the headache is preceded by auras that persist for up to 1 hour. These transient symptoms are characterized by an unexpected onset and a slow expansion of the area affected by the dysfunction followed by gradual resolution. Functional neuroimaging in humans during the opening minutes of spontaneous migraine attacks has demonstrated that decreases in relative cerebral blood flow occur in areas of the occipital cortex. In one case, the beginning of a migraine attack was fortuitously captured using PET and ¹⁵O-labeled water. A bilateral spreading area of decreased blood flow was observed that started in visual associative cortex (Brodmann’s areas 18 and 19) within a few minutes after the onset of a bioccipital throbbing headache. The hypoperfusion progressed anteriorly with time across vascular and anatomic boundaries.³³ Although the subject’s difficulty in focusing on a visual target during a part of the study has been interpreted as an atypical migraine aura, it is difficult to draw conclusions about more typical auras because neither scintillations nor a scotoma were reported and because the subject had previously only attacks of migraine without aura.