Cerebral Hemispheres 2



The neurobiology of headaches

December 15, 2015

Headaches are one of the most common neurological complaints; most people will experience headaches at some point in their life and close to 50% of the world's population is estimated to be suffering from a headache disorder at any point in time. The World Health Organization considers headaches to be one of the most disabling conditions people experience based on the impact chronic headaches can have on quality of life.

There are more than 200 different types of headaches, which are broadly classified as either primary or secondary headaches. Primary headaches are headaches that are not clearly associated with any disease or structural disturbance; they are often benign and make up the majority of headache complaints. Secondary headaches are less common, but also can indicate a much more dangerous situation as they may be a symptom of some underlying problem like an infection, injury, stroke, or tumor. While secondary headaches are not always serious, they are more likely to be than primary headaches.

Causes of primary headaches

There are several categories used to classify primary headaches; they include: migraine, tension-type headache (TTH), trigeminal autonomic cephalalgias (TACs), and other primary headache. Each of these categories also contains a number of headache subtypes. Migraine and TTH are the two most common types of primary headaches, while TACs are rare and are only estimated to affect about 1 in every 1000 people. Thus, this section of the article will focus on the more common primary headache types: TTH and migraine.

Tension-type headache (TTH)

TTH is the most common type of primary headache and chronic TTH is the most prevalent headache disorder; up to 80% of people are likely to experience at least one TTH in a given year and around 40% of the world's population is estimated to be suffering with TTH disorder. The symptoms of TTH involve a mild to moderate intensity headache that affects both sides of the head and usually feels like pressure or tightness around the head. Some patients describe TTH as feeling like their head is "in a vice."

Although the pathophysiology of TTH is not fully understood, it is thought to involve aspects of both the peripheral and central nervous systems. Peripherally, patients who suffer from TTH display abnormalities in the sensitivity of the muscles associated with the head, which tend to be more tender and sensitive to pain. For reasons that are unclear, these muscles are often harder in TTH patients as well; this hardness is also associated with increased tenderness and pain, and might indicate excessive contraction of the head muscles.

Although numerous studies have documented the increased tenderness and hardness of the muscles of the head in TTH patients, it is still uncertain what sort of stimulus might act as the "trigger" to cause the generation of excessive pain signaling from these muscles. A number of potential causes have been identified, such as sustained muscle contraction like that seen with teeth clenching, abnormalities in blood flow, and signaling initiated by inflammatory chemical messengers like serotonin. It is unclear at this point, however, if any of these mechanisms is a common denominator in the onset of all TTH.

It is also thought there may be some disruption in central pain pathways in TTH, and that this type of disruption may be especially important for the transition of infrequent TTH to chronic TTH. One hypothesis is that the increased muscular pain sensations mentioned above cause excessive activation of spinal cord and brainstem neurons involved in pain signaling as well as activation of neurons in areas of the brain that are involved with processing pain, like the thalamus and somatosensory cortex. This exaggerated activity may also cause pain pathways to become highly sensitized, leading them to be activated in response to smaller and smaller degrees of stimulation. Additionally, it is thought that mechanisms involved with pain inhibition may begin to fail to suppress pain signaling, compounding the effect.

In addition to these proposed mechanisms, it is thought there are a number of other potential influences on the occurrence of TTH. For example, studies suggest TTH has a genetic basis, and there also seems to be a relationship between psychological stress, anxiety, and depression and the occurrence of TTH. It is not clear, however, exactly how these factors may influence the pathophysiology of TTH. In other words, although there are commonalities in the genetics and/or mood state of people who are likely to experience TTH, the underlying neurobiology that causes those commonalities to lead to increased frequency of TTH is unknown. Thus, TTH is a relatively poorly understood disorder, and many questions remain about the precise mechanisms underlying TTH as well as the risk factors that make someone more likely to experience TTH.


Migraine is the second-most prevalent type of primary headache disorder, affecting more than 10% of the world's population. Migraines can sometimes be hard to differentiate from TTH, but there are some distinct symptomatic differences between the two complaints. For example, migraines tend to affect only one side of the head and are usually characterized by a throbbing or pulsating pain (as opposed to the pressure-like pain felt in TTH). Also, unlike TTH, migraines are generally made worse by physical activity and often are associated with nausea and/or vomiting. Migraine headaches can last anywhere from several hours to several days and involve a variety of symptoms ranging from autonomic problems like nausea and vomiting to sensory disturbances like extreme sensitivity to light and sounds.

There are often a variety of symptoms that occur in the hours before the onset of a migraine headache; these are referred to as prodromal symptoms. The presentation of symptoms varies significantly depending on the individual, and may involve diverse afflictions ranging from fatigue and mood changes to a stiff neck and frequent yawning. In many migraine sufferers, there is also a distinct period of neurological disturbance that occurs just before the onset of a headache. This is known as an aura, and it can include an assortment of symptoms such as: visual disturbances like flashing lights or loss of vision, numbness or tingling of the face or extremities, tremor, weakness, auditory hallucinations, or difficulty speaking.

It is thought that multiple brain regions may be responsible for the diverse group of prodromal symptoms. For example, aberrant activity in the hypothalamus may generate symptoms like food cravings and fatigue, brainstem neurons may cause neck stiffness and muscle tenderness, activity in the cortex may lead to unusual sensitivity to sensory stimulation, and other areas of the limbic system may be responsible for symptoms like depression and anhedonia. How this activity then triggers the development of a headache, however, is unclear. One hypothesis is that the activation of hypothalamic neurons can cause stimulation of neurons in the brainstem, leading to the release of substances that promote vasodilation and inflammation. These processes are associated with the stimulation of nociceptors in the meningeal layers surrounding the brain as well as with the activation of neurons associated with the trigeminal nerve, the main pain pathway for the head and face. Although it is still somewhat unclear why these relatively minor effects would result in pain signaling as intense as what is seen in migraines, it may be that migraine sufferers also have increased sensitivity in these pain pathways, causing what should be mild pain to be excruciating.

The auras that many migraine sufferers experience are also associated with abnormal waves of electrical activity in the brain, which are referred to as cortical spreading depression, or CSD. In CSD, a wave of excitation or depolarization spreads across neurons in the cortex; it is followed by a wave of inhibition or hyperpolarization. This abnormal brain activity is associated with the release of pro-inflammatory substances, which may cause nociceptors in the meninges to be activated and lead to the onset of the migraine itself.

Again, it is not clear why these patterns of activity should cause such excruciating pain, thus it is hypothesized that patients who experience migraines may also have overly-sensitive pain pathways that carry signals from the meninges and their associated arteries to the brain. The main pathway that carries such signals, called the trigeminovascular pathway, can be activated by events like CSD. Also, it appears that repeated activation can cause the pathway to begin to respond to stimuli that might not have been strong enough to elicit a response in the past. This hypersensitivity may be responsible for the chronic nature of migraine that is experienced by many sufferers of migraine disorders.

Causes of secondary headaches

While primary headaches are not clearly caused by some other disease, disorder, or otherwise underlying problem, secondary headaches can generally be associated with a distinct causal factor; this can be anything ranging from the overuse of certain medications to the presence of a brain tumor. Secondary headaches are less common---but potentially more serious---than primary headaches. They can be due to a number of different mechanisms depending on the primary cause of the headache. If due to a brain tumor, for example, the cause of the headache might involve increases in intracranial pressure driven by the presence of an abnormal growth; this increased pressure can activate the trigeminovascular pathway. Medication-overuse headache, another form of secondary headache that usually stems from the regular use of medications like opioid drugs to prevent headaches, can involve alterations in neurotransmitter systems among other potentially pathological neurobiological changes. Thus, the mechanisms underlying secondary headaches are as diverse as the conditions they are associated with, and for the most part our understanding of their pathogenesis is not complete.

Poorly understood afflictions

Despite the fact that headaches are an affliction that people have written about since the beginnings of recorded history, there is still much to be understood about how they occur. The mechanistic explanations for our most common headache disorders remain slightly vague and, in some cases, relatively speculative. It is hoped, however, that with continued study and the application of newer methods of investigation in neuroscience (e.g. neuroimaging), we will be able to understand this diverse collection of disorders more thoroughly, leading to better treatments for headaches and headache disorders.

Burstein, R., Noseda, R., & Borsook, D. (2015). Migraine: Multiple Processes, Complex Pathophysiology Journal of Neuroscience, 35 (17), 6619-6629 DOI: 10.1523/JNEUROSCI.0373-15.2015L. Bendtsen, A. Fumal, J. Schoenen (2011). Tension-type headache: mechanisms Handbook of Clinical Neurology DOI: 10.1016/S0072-9752(10)97029-2


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