Biology 202
2003 First Web Paper
On Serendip

As a disorder reaching nearly every culture, historic and contemporary, headache has been experienced in some form by the majority of the human population. Despite its relative age and prevalence, we have yet to fully ascertain either its cause, its organization, or its cure, and continue to suffer everything from quotidian tension-type headache to cluster or "suicide"-type headache with little substantial relief. So just what is it we know about headache? Broadly, headache is largely understood in terms of its external characteristics, that is, its symptoms and their effects on the sufferer. Headache is described as "a throbbing, pulsating or dull ache, often worsened by movement and varying in intensity [that] can be a disorder unto itself, such as migraine, or a symptom of another disorder ranging from a head injury to a brain tumor" (1). The term headache comprises a wide range of subtypes, the most common and studied of which are tension-type, migraine, and cluster headache (1). Of focused attention in this paper is migraine headache, a disorder now afflicting between 23 and 28 million Americans, about 60% of whom go undiagnosed (1).

Historically, migraine and its symptoms have appeared in popular as well as medical literature for more than 1000 years (1). Arguments addressing the nature of migraine pain have thus been long debated, particularly as to whether it was the result of "a disorder of blood vessels (vascular) or of the brain itself (neural)" (2). As early as 1873, Edward Liveing published a theory of the link between migraine and other neurological disorders, including insomnia, epilepsy, vertigo, and vasovagal faints. He asserted with surprising accuracy what contemporary researchers are still discovering: that migraine and other neuroses are a dysfunction of the nervous system originating in the cerebral cortex of the brain (2). Now, hundreds of years later, researchers are engaged in the continuing search for proof of the true pathogenesis of migraine and its cure. What has thus far been accepted is the rather vague definition of migraine headache as "a primary episodic headache disorder characterized by various combinations of neurological, gastrointestinal and autonomic changes" (1). Yet for its pervasiveness and deleterious effects, what do we truly understand about migraine headache? How is migraine related to other neurological dysfunction? Is there a cure? if so, how can it be found?

That which is most understood about migraine is of course that which is most readily observed and documented--its manifest symptoms. Previously lacking the objective means of discovering the underlying cause, researchers were constrained to understanding headache "by analyzing its symptoms" (3). Migraine headache has thus been divided into two types according to the accompanying symptoms: common migraine, which affects the majority of sufferers, and classical migraine, which affects about 15% of migraine patients (3). Both common and classical migraine are associated with extreme throbbing pain that is often unilateral (one-sided), nausea, and "exquisite" sensitivity to light (photophobia) and sound (sonophobia) (3). Those with classical forms of migraine, however, experience an additional symptom, "a distortion of vision that can be hallucinatory in nature" known as a migraine "aura" (3). Both classical and common migraine follow a common symptomatic pattern once triggered, lasting a total of between 12 to 24 hours. The pattern of migraine behavior is divided into four stages: in classical migraine, symptom progression begins with the prodrome, leading to the aura, the headache, and then the postdrome; common headache follows the same path without the experience of an aura (1).

The migraine prodrome occurs in the 24 hours preceding the headache stage and consists of feelings of extremes of euphoria and unbridled energy or lethargy and depression, with the possibility of "vague yawning," or distinct food cravings or aversions (2).

In classical migraine, the prodrome is followed by the aura, which arises before or during the headache, usually lasting about 30 minutes. The aura is characterized by visual sensations of "flashing lights, zigzag castellations, balls or filaments of light," or metamorphopsia, where objects appear distorted and out of proportion (2). The sufferer's hands may feel swollen, or her tongue too large for her mouth (2). These disturbances are thought to result from dysfunction in the parietal and occipital lobes of the brain; they have also been credited as the possible inspiration for "the grotesque experiences of Lewis Caroll's Alice in Wonderland," as Caroll was known to suffer from headache (2).

The next stage in both classical and common migraine is the headache itself, sometimes centered on the eye or temple, or beginning as a tightness at the back of the head and spreading slowly into a one-sided pain. The pain is described as throbbing or pulsating, but may also occur as "a non-specific dull ache" or a band of pressure. Movement or exertion worsens the discomfort, and nausea and vomiting may occur at the height of pain (2).

Finally, the headache is proceeded by the resolution phase, the postdrome, marked by "diminished headache intensity" in company with "a sense of relief--almost euphoria in some," though there may be "a vague bruised aching in the head and general tiredness" (2).

Triggers of migraine are much less well understood than the symptoms they cause--researchers are unable to reach a consensus on which factors consistently trigger migraines, primarily because there is in fact little such consistency. The factors most frequently blamed include hormones, insomnia, hunger, or changes in barometric pressure, though recurrent triggers vary across individual sufferers (4). Of the identified migraine triggers, two in particular could lead to new observations in the theory of migraine: hormone fluctuation and food craving/aversion. The implication of cycling drops in estrogen levels in migraine has led to an increasing body of research and speculation about women and migraines (4). In the effort to explain the pronounced prevalence of migraine among females, researchers have noted the development of significantly higher rates of migraine in girls than boys during puberty, the increasing difficulty of managing migraine during the premenopausal period, and the worsening effect of oral contraceptives and estrogen replacement therapy on migraine occurrence (4). The result of migraine from falling estrogen levels may be indicative of the close correlation between hormones and the neurotransmitters involved in migraine dysfunction. Because estrogen is involved in regulating neurotransmitter action in priming blood vessels to receive serotonin, when estrogen drops, the receptiveness of blood vessels to serotonin may drop as well, causing both migraine and depression-like symptoms.

Certain foods such as chocolate, coffee, red wine, cheese, or fish have also been identified as triggers in the past, though some researchers now believe dietary factors to be related to "suggestion and psychological conditioning" or "neighborly suggestion and pseudoallergy," rather than actual food-specific sensitivity (2). This dismissal however, may not consider closely enough the relation between hormonal changes and unusual attitudes toward specific foods often experienced during periods of hormonal fluctuation, such as menstruation or menopause, and seen in the prodromal stage of migraine. Such a link may be indicative of the role of particular foods and their biological effects on brain chemicals associated with the sensation of emotional sorrow or pleasure. The unusual attitudes toward food seen in the prodromal stage of migraine, along with the co-occurring disruptions of emotions (euphoria, lethargy, depression), may be a clue about the possible relationship of migraine not only to neurotransmitter regulation in the blood vessels, but about food and its ability to affect migraine-related brain chemistry. Despite assertions, food may well be a noteworthy trigger of migraine attack worthy of exploration, potentially able to reveal further insight into the neurological activity of neurotransmitters, food, and pain/pleasure in migraine headache.

Beyond what is externally manifest during migraine headache, what is known of the internal pathogenesis (cause) and pathophysiology (changes associated with dysfunction)? At present, knowledge of headache, migraine or otherwise, is relatively limited, and what is known has been only recently discovered through new brain-imaging technology. Previously, little to no information on brain activity during migraine was available, and theories of the disorder's cause and internal manifestation were vague and unsubstantiated. The most widely held past theory believed stress to be the main contributor to all forms of headache, and was supposed to somehow act on the arteries of the brain, thereby constricting blood vessels and reducing oxygen flow to the brain. The vessels were said to then inexplicably contract and irritate the nerves of surrounding arteries, which subsequently caused the sensation of headache pain (the brain itself does not feel pain) (4). More recent researchers now question the theory, reasoning, as did neurologist Neil Raskin, that: "If it were true, we would get a headache after running around the block," which also causes blood vessels in the brain to contract (4).

How then does the brain experience pain? If the brain itself does not feel pain, why do headaches produce severe head pain? The answer (at present) lies with the structures of the brain that do feel pain, which include the meninges (the three membranes that envelop the brain and spinal cord: the pia mater, dura mater, and arachnoid membrane), arteries and veins, paranasal sinuses, the eyes, and the cervical spine (2). The mechanisms causing head pain are the distension, inflammation, and traction of the blood vessels, ventricles, and dura matter (2). When pain sensitive structures are irritated, the tirgeminal nerve, the sensory pathway between the head and neck, acts as the pain conduit. Specifically, pain is run from the nerves that supply pain-sensitive structures at one end, to the upper three cervical nerve roots at the other, where nerves are sent up into the face and scalp (2). The location and function of the trigeminal nerve in the brainstem could account for the location of pain around the eye or temple in migraine headache and the sensation of unilateral throbbing pain of migraine (3). In experimental studies this theory has been supported by the parallel pain experienced when researchers irritate the blood vessels of the brain (6).

Revised notions have therefore begun to suspect that blood vessels themselves are more likely the "victims" of headache, rather than the cause, as originally argued (3). One of the first experiments to show such evidence for a different headache pathogenesis found that by irritating the brains of laboratory rats (whose trigeminal stimulation occurs very similarly to humans') with a chemical or probe. The result was an observed wave of electrical impulses through the brain, followed by reduced electrical activity that "spread out from the point of contact like ripples on a pond" (3). This experimental approach was next tested with human brains, this time using positron-emission topography to observe resultant activity. The result was the same--an electrical wave that researchers subsequently termed cortical spreading depression (CSD) seemingly sparked by the firing of abnormally excitable neurons at the back of the brain (7). These impulses were seen to spread across the cerebral cortex of the brain down the brainstem, where important pain centers are located, and to activate afferent (sensory) neurons through the trigeminal nerve (7), (8). As the wave passes, blood flow in the brain increases, then sharply drops--the pain of headache is thought to result from the activation of the brainstem and the resulting dilation of blood vessels (8). This drop may result from signals from the hypothalamus, itself influenced by such triggering factors as seasonal patterns, diurnal and biological mood swings, fatigue, or hormonal fluctuation (6)--all of which are suspected prompters of migraine pain, and interestingly, often related to depression as well. The stimulation of nerve cells in the brain stem by CSD thus increases blood flow to the scalp and face through a parasympathetic reflex (called the trigeminovascular reflex). Here, the neurotransmitter serotonin, along with norepinephrine, is implicated as the likely chemical messenger between the neurons originating in the brain stem, telling blood vessels to dilate or contract (3). This new migraine model thereby attempts to answer the question of whether headache pain is vascular or neurological by implicating them both in a cause and effect relationship called the "trigeminovascular reflex" (9).

With a growing knowledge of what underlies head pain, what then accounts for the often implicated emotional pain of migraine symptoms? Among researchers studying migraine headache in patients, "there is a consensus that migraine sufferers have a higher risk of anxio-depressive disorders than the general population," but the nature of the link remains uncertain (10). The relationship may be a result of chance, one disorder can cause the other, for example, or they may each be incited by common environmental factors, or there may be a common biology underlying both conditions (as some researchers think most likely) (11). Interestingly, not only is depression often seen in patients who experience migraine, but many migraine symptoms mirror similar features of depressive and anxiety disorders. The euphoria of the prodrome and postdrome stage, as well as the pronounced lethargy of the prodrome echo in miniature the drastic mood shifts of bi-polar depressive disorder and some personality disorders. This may be explained by the similarity of brain activity found in depression and migraine, including activity in the hypothalamus, which is implicated in the hormonal and mood regulatory functions of the limbic system; and the neurotransmitter serotonin, which is linked to depression and the sensation of emotional suffering or pleasure. According to researcher Fred Shetell, depression is mediated by the same neurotransmitters, and "migraine and depression often occur in the same people...More than 70% of people with migraine have a close relative who also suffers from the disorder" (9).

The significance of the relation between migraine headache and serotonin, is further evidenced by the "significant comorbidity between chronic headache and psychological distress" (5). Both "frequent headache and frequent disability are associated with depression, anxiety, and impaired quality of life;" while "headache associated with anxiety or depression tends to be more severe and often requires supplementary psychological treatment in addition to headache therapy" (5). In a study by published by the medical journal Cephalalgia, researchers found a significant link between abnormal perceptual experiences found in migraine aura and mood changes, particularly those of increased depression and irritability. The spread depression of cortical electrical activity was concluded to be responsible for temporal lobe and limbic system dysfunction experienced in both migraine and depressive disorders (5). Further, in a study by Guillem, Pelissolo, and Lepine, after examining the lifetime prevalence of major depression in migraine sufferers, it was found that 34.4% of migraineurs experienced clinical depression, in contrast to only 10.4% in those without migraine. For bipolar I disorder, the prevalence was 6.8% among people with classical migraine, versus 0.9% in those without (5). This evidence opens a new avenue of discussion, and begs for more investigation. Increased understanding of the neurological ties of migraine and depression could aid in the development of more comprehensive knowledge of migraine headache and how it can be treated. Beyond migraine, better comprehension of such neurological activity would also represent significant progress in the understanding of brain function and dysfunction in a more general sense.

Finally, the question most crucial to migraine sufferers: is there a cure to eliminate any and all future migraine pain? and if so, when will it be found? Currently, a cure for migraine headache pain has yet to be found, though patients can seek a variety of treatments, including psychophysiological therapy, physical therapy, and pharmacotherapy (5). Pharmacotherapy is the most widely used method, whose popular drug treatments are classified as either prophylactic (preventative), analgesic (pain reducing), or abortive (to reduce acute pain) (4). While no cure has yet been found, the discovery of CSD activity in the brain and the added understanding of the headache process to which it has contributed signals a significant advance in headache research. Studies of CSD could be useful in prophylactic migraine treatment by detailing how or why headache is triggered and just how "CSD activates the trigeminal nerve" (2). The recent discovery of a gene apparently linked to migraine heredity may also offer another step toward more effective treatment. In January of 2003, Italian scientists discovered a gene, ATP1A2, in human chromosome 1 that was linked to severe migraines in a four-year study of six generations of a migraine-prone family. The scientists believe a mutation of the gene causes "a malfunction of the pump that shifts sodium and potassium through the cell" (10). The presence of the mutant gene was associated with migraine pain, the sensation of tingling hair, and the perception of flashing lights commonly associated with migraine aura (10). If such a gene can be definitively linked to the source of migraine pain, development of more direct and effective preventative treatment could become a significantly nearer reality.

While much remains unknown about migraine headache, new research and experimental brain-imaging tools are actively seeking deeper and more comprehensive knowledge. Advances may be slow in the understanding of a disorder that is likely as old as man himself, but with each new discovery about the internal structures and functions of the brain, we come closer to better treatment, maybe even a cure. Because of the vastness of the brain's complexity, understanding one manifestation of dysfunction, such as migraine, may well also provide new leads to understanding other closely linked neurological disorders, such as depression or anxiety. Perhaps migraine disorder is a single feature in a chain of intertwined, co-occurring disorders, or perhaps it stems from a malformed gene passed through familial generations. With as much as remains unknown, each possibility can lead to fascinating new relationships and functions of the brain previously unimagined.

References

1)Headache, by Stephan D. Silberstein, on the Encyclopedia of Life Sciences web site.

2)Migraine, by J.M.S. Pearce, on the Encyclopedia of Life Sciences web site.

3) Brownlee, Shannon. The Anatomy of a Headache. U.S. News & World Report, 31 July 1989.

4)Migraine, by The Merck Manual of Diagnosis and Therapy on the Merck Manual web site.

5)Identification of Patients with Headache at Risk of Psychological Distress, by D.A. Marcus, Headache, May 2000 on the Web of Science web site.

6)Intrinsic Brain Activity Triggers Trigminal Meningeal Afferents in a Migraine Model , by Hayrunnisa Bolay, Uwe Reuter, Andrew K. Dunn, Zhihong Huang, David A. Boas, and Michael A. Moskowitz, Feb 2002 on the Nature Medicine web site.

7)New Research Could Open Doors to Better Migraine Treatment, by CNN on CNN.com.

8)New Understanding into the Mechanics of Migraine, by Kathryn Senior, Lancet, 9 Feb 2002 on Lexis-Nexis.

9)Sheftell, Fred D. Migraine Headaches. Scientific American, Summer 1998.

10)Italian Scientists Discover Migraine Gene , by Rachel Sanderson, 21 January 2003 on MEDLINEplus.

11)Inheritance of Cluster Headache and its Possible Link to Migraine, by L. Kudrow, Headache, July 1994 on the Web of Science web site.

12)Prevalence of Frequent Headache in a Population Sample, by J. Liberman, R. B. Lipton, Al Scher, and W. F. Stewart, July-August 1998 on the Web of Science web site.


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