Migrain
Phases of Migraine
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Premonitory Phase:
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Timing: This phase occurs hours to days before the onset of the actual headache.
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Symptoms: Non-painful symptoms characterize this phase, and examples include neck stiffness, yawning, thirst, and increased frequency of urination.
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Neurological Involvement: Functional imaging studies have shown early involvement of subcortical structures, including the hypothalamus, substantia nigra, dorsal pons, and various limbic areas.
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Connectivity Changes: Recent research indicates altered hypothalamic-brainstem functional connectivity during this phase, occurring before the onset of pain.
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Prevalence: The prevalence is reported to be around 84%, although the exact figure is uncertain due to limited large-scale population-based trials.
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It's worth noting that migraines can vary from person to person, and not everyone experiences all three phases. Some individuals may not have a premonitory phase, and their migraines may start directly with the aura or pain phase.
BIOLOGICAL MEDIATORS OF PREMONITORY SYMPTOMS
Studies suggest a role of neuropeptide Y and dopamine (as well as orexins, somatostatin, and cholecystokinin), all secreted through the hypothalamus, in mediating premonitory symptoms associated with migraine and a role in trigeminal nociception.
Neuropeptide Y, a substance secreted by the hypothalamus, is involved in feeding, appetite regulation, pain, and circadian rhythms. This neuropeptide Y may be involved in both pain and appetite changes in migraine (systemic neuropeptide Y administration inhibited trigeminovascular complex).
Somatostatin, a hypothalamic hormone, is implicated in the primary headaches disorder as octreotide (somatostatin analog), is helpful in cluster headaches and not migraines. Cholecystokinin expressed in the ventromedial thalamus suggests a hypothalamic role in mediating feeding and appetite changes associated with migraines.
Human Neurophysiology
Frontal cortical areas and their limbic connections are likely responsible for mediation in concentration difficulty, fatigue, and emotional changes during the premonitory phase. Visual cortical responsiveness is increased preictally as supported by the increase in the component of visual evoked potentials in the subjects.
Human Functional imaging studies
Altered hypothalamic activity occurs in response to trigeminal nociceptive stimulation (using intranasal ammonia), up to 24-hours prior to the onset of migraine headache, as observed in the functional imaging studies.
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Functional MRI activity within the trigeminal nucleus caudalis (area of convergence of sensory afferent input from head and neck) following trigeminal pain stimulation changed and could predict the next headache attack.
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Early activation of the hypothalamus, dorsolateral pons, and several cortical areas have been demonstrated by PET (positron emission tomography) during the premonitory phase.
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Functional correlation with neural basis demonstrates:
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Cingulate cortex activation mediating mood and cognition
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Hypothalamic activation mediating yawning, thirst, frequency of micturition, and neck discomfort.
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Individuals with photophobia showed activation of the occipital cortex
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Nausea showed activation of the brainstem (the region of the nucleus tractus solitarius)
Therapeutic Avenues
Domperidone and a triptan have been trialed during the premonitory phase.
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10-40 mg of domperidone taken in premonitory phase aborted pain onset in 30 to 63 % of attacks. 30 mg prevented the headache onset in 66% of attacks (compared 5% in placebo)
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Naratriptan 2.5 mg was found to prevent 60% of the migraine headaches when given in the premonitory phase (in an open-label study)
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Orexins have emerged as a hypothalamic neurotransmitter of interest, given their role in sleep (and strong association between sleep and migraine). Filorexant (orexin receptor antagonist) trial was though unsuccessful.
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Octreotide (somatostatin analog) has a beneficial effect in the treatment of cluster headaches. Somatostatin, secreted by the hypothalamus is known to modulate trigeminovascular pain signaling.
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Melatonin is released from the pineal gland, in response to hypothalamic input but the melatonin receptors are present in the suprachiasmatic nucleus of the hypothalamus. Melatonin has been linked to primary headache disorders because of its association with sleep and circadian rhythm. Although melatonin is commonly used in cluster headaches, conflicting evidence exists in its efficacy in the prevention of both adult and pediatric migraine.
The Full Story
The Migraine Postdrome:
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The postdrome is the period between the resolution of the throbbing headaches and when the patient feels back to normal. 81% of the subjects in the prospective study had at least one non-headache symptom. The average duration is 18-25 hours.
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The clinical features may be grouped into (1)Neuropsychiatric, (2) Sensory, (3) Gastrointestinal, and (3) General symptoms. Tiredness, concentration difficulty, and neck stiffness are the most typically reported post-drome symptoms.
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The key structure involved in the perception of headaches includes the large intracranial blood vessels and duramater; the peripheral terminals of the trigeminovascular system that innervates these structures; the caudal portion of the trigeminal nucleus, which extends to the dorsal horns of the upper cervical spinal cord and receives input from the first and second cervical nerve roots( the trigeminocervical complex); and the pain modulatory systems in the brain that receives input from the trigeminal nociceptors.
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The dysfunction of the neuromodulatory structures in the brainstem is thought to be a core component in the pathophysiology of migraine.
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Locus coeruleus (major noradrenergic nucleus) has a vital role in the regulation of cortical function and is known to modulate responses to afferent traffic. During acute migraine attacks, based on PET studies there is an activation of this region and it may play a dominant role in the postdrome.
Cortical excitability may indicate the chronicity of the disease. Evidence that the brain in patients with migraine is hyperexcitable (to a variety of stimuli), suggests that neural depolarization (presumed to be initiating event in migraine aura) is more easily triggered. Visual phosphenes in patients with migraine (as compared to without migraine) are more easily triggered by the lower level of transcranial magnetic stimulation, supporting the notion of brain hyperexcitability. Neuronal excitability can be increased by various mechanisms brought on by genetic mutations.
Postdrome and premonitory phases have broadly similar symptoms and thus it can be hypothesized that they share a common neural network. Posterolateral hypothalamus, midbrain tegmental area, periaqueductal gray, dorsal pons, and cortical areas such as frontal, temporal, and occipital regions are activated based on functional imaging studies.
Widespread reduction in brain blood flow in postdrome has been demonstrated by functional imaging using arterial spin labeling. Diffuse cortical involvement is postulated especially of the frontal lobes and hypothalamus (by Blau).
PATHOPHYSIOLOGY MECHANISMS OF THE POSTDROME
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Locus coeruleus (a noradrenergic nucleus located in the dorsal pontine tegmentum) is a major source of norepinephrine to the cerebrum, brainstem, cerebellum, and spinal cord. It is the first system that becomes involved during stressful events such as pain processing, behavioral modification, and stress reactivity.
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The existence of reciprocal circuits between locus coeruleus, the neocortex, diencephalon, limbic system, and spinal cord emphasizes its widespread impact on neuraxis.
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Locus coeruleus activation leads to widespread vasoconstriction mediated by the alpha-2 adrenoceptor mechanism. This may serve as a pain modulatory mechanism but as a consequence, may lead to postdromal symptoms.
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Cortical spreading depression may be another mechanism behind the reduction in regional blood flow in postdrome. It is proceeded by a fast network of oscillations (suggesting brief hyperexcitability), followed by complete suppression of neuronal activity, lasting several minutes followed by complete recovery. Cortical spreading depression usually silences spontaneous and evoked electrical activity for 5-10 minutes. In certain pathophysiological states such as hypoglycemia, hypoxia, and ischemia, cortical spreading depression can occur spontaneously and can be prolonged in nature. Astroglial function hampering may lead to increased susceptibility to cortical spreading depression.
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