Diencephalic and brainstem mechanisms in migraine

Key Points

  • Migraine is a chronic and disabling brain disorder that typically manifests as attacks of one-sided, often throbbing head pain that is worsened by movement and is associated with nausea and sensitivity to light (photophobia) and sound (phonophobia).

  • Migraine is thought to involve activation of the trigeminovascular system, which includes the efferent projections to the pain-producing dura mater and large intracranial vessels, and the afferent projection to the central trigeminal nucleus caudalis (TNC). It is a pivotal relay centre that passes nociceptive information from the cranial vasculature to the brainstem and higher processing centres.

  • Several studies have demonstrated that structures within the brainstem, midbrain and forebrain — areas that are known to be involved in the modulation of the trigeminovascular system — are active during spontaneous migraine. This suggests that dysfunction within these regions may be responsible for a migrainous phenotype.

  • In the pons, the superior salivatory nucleus (SuS) has a reflex connection with the TNC and provides the cells of origin of the parasymapathetic outflow to the cranial vasculature. Activation contributes to the autonomic symptoms in primary headache and has now been shown to also activate and exacerbate neuronal firing in the TNC.

  • In the midbrain, the ventrolateral periaqueductal grey and rostral ventromedial medulla provide descending control of trigeminovascular nociceptive responses, controlled by 'on'- and 'off'-cell activation. Additionally, connections with hypothalamic, thalamic and limbic nuclei, which are involved in homeostatic processes, suggest that 'on'–'off' cell activation, or the dysregulation of these cells, may be involved in triggering migraine and may contribute to migrainous symptoms.

  • In the forebrain, the hypothalamus is involved in the control of the sleep–wake cycle, feeding, thirst, urination and arousal — behaviours that are altered during premonitory symptoms. Disruption to the regular functioning of these behaviours can also serve as triggers for migraine. Bidirectional connections with the SuS may provide a link between the potential site of origin of migraine triggers, premonitory symptoms and other migraine symptoms, and descending modulation of trigeminovascular nociceptive traffic.

  • The thalamus is a major centre for processing nociceptive information. Sensitization of third-order trigeminovascular nociceptive neurons in thalamic nuclei is likely to contribute to the cutaneous allodynia that is experienced by patients. Sensitized neurons of the posterior thalamus that receive projections from areas of the visual cortex respond to bright light with exacerbated firing. This may provide a neural explanation for the photophobia that is exhibited by patients who suffer from migraine.

  • We believe that the explanation that best accounts for the multifaceted migrainous symptomology is a dysfunction of the brainstem or diencenphalic nuclei that process nociceptive inputs of the craniovascular afferents. The bidirectional connections of the many brainstem and diencephalic nuclei mean that dysfunction can create a brain state that produces many simultaneous symptoms. The next best theory involves a sequential sensitization of trigeminovascular synapses up to the thalamus that requires an initial peripheral nociceptive event. This cannot explain many centrally mediated migraine triggers or the premonitory symptoms that precede any pain.

Abstract

Migraine is a common and complex brain disorder. Although it is clear that head pain is a key manifestation of the disorder for most patients, what drives the activation of neuronal pain pathways in susceptible patients is less obvious. There is growing evidence that migraine pathophysiology may, in part, include dysfunction of subcortical structures. These include diencephalic and brainstem nuclei that can modulate the perception of activation of the trigeminovascular system, which carries sensory information from the cranial vasculature to the brain. Dysfunction of these nuclei, and their connections to other key brain centres, may contribute to the cascade of events that results in other symptoms of migraine — such as light and sound sensitivity — thus providing a comprehensive explanation of the neurobiology of the disorder.

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Figure 1: Neuronal pathways involved in migraine pathophysiology.
Figure 2: Descending modulation of trigeminovascular nociceptive transmission through midbrain nuclei.
Figure 3: Descending modulation of trigeminovascular nociceptive transmission by hypothalamic nuclei.
Figure 4: Trigeminovascular and visual inputs to the thalamus and visual cortex.

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Correspondence to Peter J. Goadsby.

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P.J.G. is a paid member of the boards of the following companies: Allergan, Colucid, MAP Pharmaceuticals, Merck Sharpe and Dohme (MSD), Neuralieve, Neuraxon, ATI (Autonomic Technologies Incorporated), Boston Scientific, Coherex, Eli-Lilly, Medtronic, Linde gases and Bristol Myers Squibb (BMS). In addition, he is a paid consultant for Pfizer and Air Products and has provided paid expert testimony for MedicoLegal advice. The institution at which P.J.G. works receives grant funding from GlaxoSmithKline, MAP, MSD, Neuralieve, Boston Scientific and Amgen. P.J.G. has also received payment for lectures from MSD, Pfizer, Allergan and Mennarini, and has been paid to provide educational slides to the American Headache Society.

Glossary

Aura

Fully reversible neurological symptoms that typically occur before a migraine and that move from one part of a limb, or of the body, to another. These symptoms can include homonymous visual symptoms (that is, flickering lights, spots or lines, or complete loss of vision), sensory symptoms (that is, pins and needles, or numbness) and dysphasic speech.

Brainstem

The most posterior (stem-like) part of the brain, adjoining the cerebral hemispheres. The brainstem is structurally continuous with the spinal cord and comprises the pons, medulla oblongata and midbrain.

Cortical spreading depression

(CSD). A slowly propagating wave (2–6 mm min−1) of sustained strong neuronal depolarization that generates transient and intense spike activity, followed by neural suppression that can last for several minutes.

Trigeminocervical complex

(TCC). A group of spinal cord regions that include the trigeminal nucleus caudalis in the cervicomedullary junction and the superficial layers of the high cervical region dorsal horn at the C1 and C2 level of the spinal cord.

Quintothalamic tract

Also known as the trigeminothalamic tract. The tract that carries sensory information from the head and face to the thalamus through the trigeminal nucleus.

Positron emission tomography

(PET). A nuclear imaging technique that produces three-dimensional images of the brain by detecting photons that are emitted by a positron-emitting radionuclide tracer.

Midbrain

Also known as the mesencephalon. The region that is situated between the pons and the diencephalon, and that includes the periaqueductal grey (PAG).

Hyperaemia

Also known as hyperperfusion. An increase in blood flow.

Oligaemia

Also known as hypoperfusion. A decrease in blood flow.

Diencephalic structures

Structures of the diencephalon, which is the posterior part of the brain. The diencephalon is anterior to the brainstem and includes the hypothalamus, thalamus, metathalamus and epithalamus.

Trigeminal autonomic cephalalgias

(TACs). Primary headache disorders that are characterized by unilateral head pain occurring in association with ipsilateral cranial autonomic features. There are three major pathophysiological features: trigeminal distribution of pain, cranial autonomic features and an episodic pattern of attacks.

Central sensitization

An enhanced response of central neurons by activation of peripheral nociceptors.

Allodynia

The perception of pain from a stimulus that is normally considered innocuous or a stimulus that does not normally produce pain.

Referred pain

In the context of headache, referred pain is the area of the head where spontaneous pain is felt; in a literal sense it is pain in a location other than the site of stimulus. In the case of migraine, the stimulus is likely to be either central or at the very least intracranial, whereas the pain is perceived in the extracranial region.

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Akerman, S., Holland, P. & Goadsby, P. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12, 570–584 (2011). https://doi.org/10.1038/nrn3057

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