Migraine and Puberty: Potential Susceptible Brain Sites

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Puberty is a sensitive and critical period for brain development. The relationship between developmental processes in the brain during puberty and the onset of migraine disease in relation to the potential sites of susceptibility in the brain remains largely unknown. There are few data on how such processes interact with each other in influencing the migraine onset during puberty or even later in adulthood. Focusing on the migraine brain during pubertal development may provide us with a “window of opportunity” both to better understand the mechanisms of the disease and, also more importantly, to effectively intervene.

Introduction

Migraine is one of the top 5 most frequent childhood diseases.1, 2 It occurs in up to 10.6% of children between the ages of 5 and 15 years, and in up to 28% of children between 15 and 19 years of age.3, 4 Compared to adults, migraine attacks in children are of shorter duration and may be bilateral or unilateral. Episodes are associated with photophobia, phonophobia, and nausea and less commonly with auras. Migraines can be seriously disabling to pediatric sufferers by impairing their quality of life, school attendance, or participation in various activities. They may also develop comorbidities such as anxiety, depression, sleep disorders, and a variety of other pain conditions.

Multiple population-based epidemiologic studies have observed that the prevalence of migraine increases with age during adolescence. However, there is a notable sex difference in the age-related presentation. Prepubertal youth males have a slightly higher prevalence of migraine compared to females, whereas after puberty, prevalence increases sharply among females and remains low in males. This pattern suggests that changes involved in pubertal development among females are critical in their having migraine. The increase in incidence among females starts during the earlier stages of pubertal development and increases rapidly,5 reaching its peak between the ages of 14 and 16 years. Incidence then gradually declines with age in females. Headache disorders can persist for a long time, and the prevalence of migraine peaks between ages 35 and 45 years, affecting 2-3 times more women than men.6, 7, 8, 9

Sex differences in the time of hormonal changes that occur during puberty and their associations with brain development may lead to the previously described differences in the risk of sex-influenced diseases, such as migraine.9 The mechanisms through which the hormonal changes during puberty may influence the phenotypic expression of migraine are not well understood, and the identification of potential sensitive or susceptible regions in the brain remains largely unknown. Moreover, there are few data concerning how such processes interact with or influence brain development during puberty.10 Understanding the underlying mechanisms of such interactions in the brain during puberty may provide a “window of opportunity” to better explain the mechanisms of the disease and also better understand how to effectively intervene. Changes in the brain during pubertal development may play a significant role in the onset of the disease, not only in childhood but also later in adulthood.

Section snippets

The Activation of Neuroendocrinal Pathways

Because hormones influence brain structure and function and because hormone secretion is governed by the brain, applied molecular neuroscience techniques can begin to reveal the role of hormones in brain-related disorders and the treatment of these diseases.11

Pubertal development is a process that is initiated by hormonal signals from the brain to the gonads. Gonadotropin-releasing hormone (GnRH) pulse generating neurons located in the arcuate region of the mediobasal hypothalamus are

Brain Reorganization During Puberty

Converging lines of evidence indicate that puberty is a sensitive period for brain reorganization.9, 21, 22, 23, 24, 25 This process involves both genomic as well as hormonal regulation of signaling pathways that influence reproductive behaviors and structures and also interact with the brain in determining its organization.9, 26, 27 The brain grows by developing synapses between the neuronal cells and subsequent pruning of the connections to get rid of unnecessary connections. During puberty,

Separation of the Effects of Pubertal Maturation From the Effect of Chronological Age on Brain Development

There are interindividual differences in different aspects of pubertal maturation such as age of puberty onset, length of puberty period (from onset to completion), and the amount of growth happening during this period. Therefore, when studying the brain during this period of life, chronological age is an inefficient variable, as there is a wide range of maturational states or levels for children of the same chronological age. Given the reorganizational changes in the brain during puberty, it

Potential Sites of Susceptibility During Pubertal Brain Development

Multiple studies have shown that cortical gray matter changes during puberty are region specific and happen predominantly nonlinearly31, 32, 33 with the peak ages for increase in the frontal and parietal lobes corresponding to the ages of puberty onset.34 The increase in white matter volume seems to be more linear.35 Age-related increases in both gray and white matter volumes are both sexually dimorphic.34, 35 Multiple abnormalities in the structure and function of the migraine brain have been

Hypothalamus

The hypothalamus is a brain structure where the nervous system and the endocrine (hormonal) system interact. The hypothalamus is composed of several nuclei, and each one controls a specific function. It is activated during spontaneous migraine attacks.44 Many of the premonitory symptoms before the onset of headache in migraine, such as autonomic symptoms, are regulated by the hypothalamus.45, 46 Recent advances in the field of migraine research have provided strong evidence for a main central

Brainstem

Dysfunction of brainstem nuclei (such as the periaqueductal gray [PAG] and dorsal rostral pons) may play a major role in migraine pathophysiology.45 Brainstem dysfunction in migraine has been evidenced by multiple studies reporting functional abnormalities in this region associated with migraine (both during and in between attacks) including increase of neuronal activity during migraine45, 48, 49, 52 as well as interepisodes dysfunction of medullary dorsal brainstem descending modulatory

Prefrontal Cortex

One of the regions commonly implicated in pain processing is the prefrontal cortex (PFC). The PFC is involved in cognitive aspects of pain such as attention, expectation, and pain memory.57 There is also an abundance in the distribution of endocrine and adrenal steroid receptors in the PFC. From a developmental standpoint, the maturation of white matter is most protracted in the PFC. White matter increases throughout adolescence, and such increases imply enhanced connectivity between spatially

Insula

Multiple studies have reported abnormalities associated with the insula in migraine.47, 59, 60, 61, 62, 63, 64, 65 The insula is involved in multiple networks and processes, including interception,66 emotion,67 autonomic function,68, 69 salience,70 and multiple sensory modalities.71, 72 Both functional magnetic resonance imaging and positron emission tomography studies have shown that the insula is activated during migraine attacks,42, 63 and there are higher levels of glutamate in the insula

Hippocampus

Hippocampus is mainly involved in learning and memory, but it is also involved in pain processing77, 78, 79, 80, 81, 82, 83 and migraine.84, 85 It is also sensitive to stress and glucocorticoids, the adrenal steroids that are secreted during stress, and plays a major role in controlling stress response through providing negative feedback to the hypothalamic-pituitary-adrenal axis (HPA axis) and regulating the glucocorticoids.86 Involvement of the hippocampus with stress response and its

Trigeminal Pathway

The trigeminal nerve is one of the major pain pathways. Changes in the interactions between the trigeminal nerve and brainstem structures (eg, PAG and dorsal rostral pons) may play a key role in migraine pathophysiology.53, 54, 56 In women, trigeminal excitability in menstrual migraine is significantly higher than in healthy subjects.96 Estrogen receptors are present throughout the trigeminovascular system, and estrogen increases the production of calcitonin gene-related peptide. This is a

Amygdala

The amygdala is part of the limbic system and is mainly involved in mediating emotions such as anger and fear. Its role in migraine pathophysiology is not clear, but it may play an important one as evidenced by recent findings including migraine-specific increased interictal functional connectivity between amygdala and insula98 as well as atypical resting state functional connectivity between the amygdala and other brain regions that participate in different aspects of pain processing in

Translating Findings in Adults to a Better Understanding of Pediatric Migraine

Although there is extensive research examining and targeting migraine among adults, pediatric migraine remains a largely understudied disorder. Despite the paucity of data, accumulative insights have been gathered in adults that need to be examined and “translated” to the pediatric population undergoing puberty. There is evidence for structural and functional changes in the adult migraine brain.42, 50, 103 Examining whether such changes develop during puberty (when the incidence of the disease

Conclusion

Identifying mechanistic links between migraine disease and pubertal development may allow for a better understanding of the mechanisms of the disease onset and progression. Because of the large sex difference in prevalence and incidence observed in adults begins around puberty, we emphasize understanding the dynamics of pubertal brain development in the context of migraine disease. Exposure of the developing brain to severe stress, or trauma, or even imbalance during pubertal development may

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