Gender, migraine and affective disorders in the

course of the life cycle

 

 

Vincenzo Guidetti, MD a

Silvia Alberton, BPsycholb

Federica Galli PhDa

Pietro Mittica, BPsycholb

Elisa Salvi, BPsycholb

 

a Department of Child and Adolescent Neuropsychiatry, University “La Sapienza”, Rome, Italy

b Faculty of Psychology 1, University “La Sapienza”, Rome, Italy

 

Corresponding author: Vincenzo Guidetti

Department of Child and Adolescent Neuropsychiatry

Via dei Sabelli, 108 - 00185 Rome - Italy

E-mail: vincenzo.guidetti@uniroma1.it

 

 

Summary

 

The relationships existing between migraine and affective disorders are still far from clear. Despite the evidence of a high prevalence, in association, of both conditions, many questions remain unanswered. To what extent is the coexistence of migraine and affective disorders, in particular depression, genetically determined? How important a role is played by pregnancy? What interactions occur between genetic and epigenetic factors?

The authors analyse all these open questions and review the state of the art on this intriguing topic.

 

KEY ­WORDS: depression, gender, hormones, life cycle, migraine, temperament.

 

 

Introduction

 

It is well known that migraine is a multifactorial disorder in which biological, genetic and epigenetic aspects are closely interwoven. Remembering the riddle that the sphinx set Oedipus, our aim in this paper is to trace the evolution of migraine and affective disorders throughout the life cycle.

The concept of the family, in particular the psychosomatic family, seems to constitute a good starting point for our discussion, and fertile ground on which to identify the main dynamics that, during the developmental period, lead a child to express conflicts and distress through his or her body. The relationship between the environment and hormones is already evident during pregnancy, when maternal stress can lead to increased levels of placental corticotrophin-releasing hormone (CRH) which can interfere with the development of the foetus and, later on, be related to impairments of temperament, learning and behaviour.

Although migraine shows no gender differences in prepubertal children, occurring equally in boys and girls, in adults it is more frequent in women; the same is true of depressive disorders.

Rates of significant depression roughly double in boys and more than quadruple in girls after puberty. The presence of significant levels of somatic symptoms also increases with increasing maturity in girls, whereas in boys levels remain almost unchanged.

Furthermore, depression and somatic symptoms in girls increase the prevalence of pain syndromes in a multivariate model.

While the association between depressed mood and hormonal changes during the transition to menopause is controversial (1), it is worth noting that after the menopause the prevalence of migraine is comparable in the two sexes; in other words, there is a return to the pattern seen in childhood and, we might suppose, a closing of the cycle (2).

 

 

Why psychosomatic?

 

Minuchin et al. (3), introducing the concept of the “psychosomatic family model”, proposed three necessary conditions for the development of psychosomatic illness in children.

First, the child possesses physiological vulnerability to a chronic illness.

Second, the family engages in four specific dysfunctional patterns of interaction: i) enmeshment or overinvolvement among family members; ii) overprotectiveness or excessive concern for each other’s wellbeing; iii) rigid or redundant interaction patterns that stifle change; iv) lack of conflict resolution or failure to resolve problems by avoiding or detouring conflict.

Third, parents involve the sick child in potentially contentious marital discussions. This triangulation is likely to be detrimental to the child's wellbeing, given that it has been reported that recruiting children in disputes in this way results in increased symptom manifestation (4-6). Minuchin et al. (3) concluded that the rigid, overprotective and enmeshed interactional patterns that characterise psychosomatic families reflect a low threshold for conflict. Some individuals, when confronted with stress, develop physical rather than neurotic or psychotic complaints and/or symptoms; to diagnose these patients as psychosomatic constitutes a rather broad application of the term “psychosomatic” (7). Psychosomatic refers to an increase in general susceptibility to physical illness. On the other hand, it is no longer possible to classify a patient as psychosomatic solely on the basis of a medical diagnosis (e.g. asthma, ulcers, colitis). The psychosomatic aspect of the diagnosis must be established in each single case on the basis of positive psychosocial criteria, since the same illnesses can be brought about by different causes and psychological factors may carry different weights in each case.

As specified by Wirsching, most psychosomatic complaints contain common elements (8): i) patients consciously suppress stressful or threatening feelings and fantasies; ii) they give the impression of composed rationality and appear particularly oriented to “thing-like”, concrete objects; iii) they avoid conflict as much as possible, as demonstrated by excessive conformity to the expectations and wishes of their environment; iv) they give the impression of normal, if not pseudonormal, social behaviour, and strongly comply with dominant sex-, age-, or class-specific role expectations; v) in stressful situations, restraint is significantly apparent.

Weakland (9) created a concept of “family somatics” referring to a type of family that denies conflicts and is, apparently, particularly harmonious. The only problem is that diseases such as ulcerative colitis, anorexia nervosa, bronchial asthma, headache, etc., are present in one, or several, members of such families. Could it be hypothesised that this is often the basic background of the migrainous child? (10-12).

 

 

Hormones and the foetus

 

The development of an individual is determined by the interaction of influences, external and internal.

The overall process of ontogenesis is not simply a battle between nature and culture, but rather a dynamic intersecting of processes occurring within a system shaped by the indissoluble link between the body and its environment. Genes and hormones are the factors that determine the biological differences between the sexes in the brain. However, while the presence of a pair of XX or XY genes causes the release of specific sex hormones which lead to the phenotypical differentiation of the gonads as male or female, it has not yet been possible to demonstrate that a similar process also acts on the brain. It is indeed unlikely that the brain develops in the same way as the gonads, given that these glands are relatively simple bodies, whereas the brain is the most complex organ in the whole body. Compared to those of the gonads, the cells that make up the brain show much greater differentiation. That said, at a very early stage in ontogenesis, and even before birth, the ovaries and testes begin to secrete sex hormones that may affect the development of the brain. In the early ’60s, Geoffrey Harris and Seymour Levine’s studies on rats showed that, in order for the brain to develop in a typical male direction, testosterone must be present in the blood during the first five days after birth. This interval is the sensitive phase in which testosterone determines the diversification of the brain as male as opposed to female. For the record, it must be pointed out that this diversification involves only the hypothalamus and, in particular, the pre-optical area controlling luteinising hormone secretion and the development of sexual behaviour. Thus, the action of testosterone during the first days of life may lead to sexual differentiation, determining a switch from female to male. We must take into account that although the brain structures start to develop in the first part of pregnancy, their development is a process that continues until late adolescence. Since the male secretes, both in intrauterine life and later, a greater amount of testosterone than females, it seems likely that any effect, due to testosterone, on the development of the brain could occur after birth. Research conducted in the ’80s, however, suggested that the exposure of the female human foetus to high levels of androgens results in a masculinisation of behaviour later in life. During the different stages of development there are periods of increased sensitivity in which the effect of sex hormones could determine phenotypical gender differences.

In girls, after menarche, the situation is more complex than it is in males, because the levels of oestrogen and progesterone change during the menstrual cycle. The brain is the organ that controls the concentration of sex hormones secreted and released into the blood: most of the time, the concentrations of these hormones in the blood remain constant, although they may vary in the course of the day and, in women, in the course of the month.

 

 

Neonatal hyperactivity, temperament and migraine

 

Maternal stress during pregnancy has been studied as a risk factor that may have developmental and health consequences persisting throughout the lifespan. Animal and human studies have demonstrated that maternal stress during pregnancy has consequences on cognition and learning (13,14), stress reactivity (15), behavioural responses to novelty (16,17), and can contribute to emotional and behavioural disturbances (17-20) in the offspring. The hypothalamic-pituitary-adrenal (HPA) axis appears to be a primary pathway by which stress affects the foetus (21,22). The activity of the HPA axis is regulated by the release of hypothalamic CRH. Foetal and maternal levels of CRH are correlated because the active peptide is released into both the maternal and the foetal circulation (23-26).

Plasma CRH is of placental origin (27). CRH has been proposed as one mechanism by which prenatal stress influences foetal and infant development (28,29). While placental CRH has a direct effect on the foetus and plays a role in foetal development and maturation (30), the effects of placental CRH on human postnatal development have not been investigated. Research in humans and in non-human primates has demonstrated that an important consequence of prenatal exposure to stress and stress hormones is an increase in fearful or reactive behaviour (16,17,22). Significantly increased levels of CRH are associated with preterm delivery (31-36). An early rise in CRH may signify a hostile environment (37) and precipitate a cascade of events that influences the foetal nervous system.

It has thus been suggested that exposure of the human foetus to CRH affects infant temperament. Indeed, foetuses exposed to lower levels of maternal CRH at 25 weeks of gestation were rated by their mothers as exhibiting less fear and distress behaviour in infancy. CRH levels at 19 and 33 weeks were not significantly associated with infant temperament, indicating that there may be a critical period in which programming influences of CRH on infant temperament can be observed (38).

These data indicate that CRH may influence foetal central nervous system (CNS) development and are consistent with the few existing studies showing that elevated CRH during the prenatal period is related to impairments in learning and behavior (29,39).

Postnatal maternal anxiety and depression were also associated with reports of infant fear and distress behaviour. However, after controlling for postpartum maternal psychological state the relation between placental CRH and infant temperament was not altered, supporting the conclusion that prenatal experiences were responsible for this association (37). The mechanisms underlying the association between placental CRH and fear and distress behaviours in infancy are unknown. One possible explanation is that CRH acts directly on regions of the brain that underlie temperament characteristics. Associations were found between CRH and infant temperament at 25 weeks’ gestation, but not at 19 or 33 weeks’ gestation, suggesting that the end of the second trimester may be a period of vulnerability to exposure to elevated levels of CRH.

Several studies in humans and in non-human primates have suggested that the foetus is more susceptible to the effects of stress during the second trimester of pregnancy (17,40).

In an interesting study that examined behaviour and cognition before birth, Wadhwa et al. (34) found that the foetuses of mothers with elevated CRH levels did less well in in vivo studies of learning in foetuses. Susman et al. (41), for example, established a relation between low levels of maternal hormones (cortisol among others) at three months’ gestation and greater aggressiveness in the same children at 3 years of age, which is in line with earlier findings on the HPA axis and antisocial behaviour. O’Connor et al. (18) found prenatal maternal anxiety to predict behavioural/emotional problems in a very large sample of children at 4 years of age. Also, Huizink et al. (42) found prenatal maternal stress, psychosocially and endocrinologically measured in a prospective study, to be related to poorer mental and motor development of the infant. Graham et al. (43) showed the infants of depressed mothers to be more irritable, and to have growth delays, higher neonatal levels of cortisol, and poorer motor and cognitive development, with the effect persisting until at least the age of 3 years.

In a study by De Weerth et al. (44), higher cortisol levels at the end of pregnancy were related to more crying, fussing and negative facial expressions in the infant during a series of routine mother-infant interactions. Supporting these observations, the mothers’ reports confirmed that these infants displayed more difficult behaviour: they had higher scores on emotion and activity.

The differences between the infants were strongest in the neonatal period. At 4/5 months of age, most significant differences had disappeared, although the infants born of mothers with higher cortisol levels still fussed more during the interactions and also had a tendency to spend more time displaying negative facial expressions. At 18 weeks postnatally, the maternal reports on temperament in the two groups of mothers grew more similar to each other, leading to disappearance of the earlier significant differences.

Developmental processes related to children’s pain, although not well understood, are of critical interest to practitioners involved in the assessment and management of children’s pain (44). Both biologically-based individual difference variables and environmental context have been suggested to play a role in infant pain response. Accordingly, Sweet et al. (45) attempted to assess their relative contributions to pain behaviour in early versus late infancy.

Children’s biologically-based reactional styles may be related to their reactions to pain. Vagal tone, defined as “the amount of inhibitory influence on the heart by the parasympathetic nervous system”, indicating the amount of autonomic arousal at rest (46), has been proposed as a physiological indicator of biologically-based reactivity; instead, temperament has been proposed as a behavioural indicator of biologically-based reactivity. It is widely viewed as a psychobiological construct in which differences in physiological processes are reflected in differences in behaviour (47). Temperamental difficulty has been found to be positively related to pain in 3- to 7-year-olds undergoing venipuncture (48), 5-year-olds undergoing immunisation (49), and 6-year-olds with abdominal pain (50). However, in younger children, relations have been less consistent.

Various prodromes identifiable as components of the periodic syndrome (PS), in particular recurrent abdominal pain, cyclical vomiting, growing pain and benign paroxysmal vertigo, can be detected as early as the second year of life in the history of children suffering from recurrent, non-organic headache.

In a retrospective study (51) of healthy children, we found that subjects who eventually developed PS frequently presented a number of behavioural and physical peculiarities characteristic of “hyperreactive” children during the first six months of life. Of the 102 subjects considered “hyperreactive”, 54 (52.9%) suffered from common migraine and in 55.5% of cases had a family history of headache in first- and second-degree relatives. Sixty-six children (64.5%) in the “hyperreactive“ group had suffered from one or more components of PS.

Hyperreactivity is known to be a frequent feature among otherwise healthy neonates and infants and seems to be a pattern of response to the inputs a neonate typically receives; hyperreactive subjects constantly show “amplified” responses compared to a control group. It can be assumed that these subjects show early altered adaptability of the CNS. This might express itself as a congenital dysfunction of the nocioceptive system and of the sensorial system, in other words, as an amplification of inputs with a general repercussion on a number of behavioural and physical parameters. Hyperreactive infants might therefore be typical “amplifiers”.

This tendency to amplification finds different modes of expression at different ages and different levels of functional development.

Various components of PS, plus common migraine, may thus emerge as different expressions of a common predisposition identifiable with the marker “amplification”. According to others, this tendency may extend to a predisposition to psychosomatic disorders in general. From this perspective, both the neurobehavioural basic equipment and the characteristics of the environment would play an important role (51).

Higher responsiveness and/or a lack of habituation to sensory stimuli of various modalities including aversive and painful stimuli (52-55) suggest that migraine may be characterised by cortical hypersensitivity and/or a lack of cortical inhibition (56,57). Hypersensitivity to aversive or noxious stimuli could also be related to sensitisation of pain pathways resulting from repeated intense nociceptive stimulation during migraine attacks (58,59). Hence, higher responsiveness to noxious stimuli, in the context of the hypothesised crossmodal hypersensitivity in migraine, may represent a useful index of vulnerability to migraine (60). Migraine has been shown to be strongly familial with substantial evidence of vertical transmission (61), suggesting a maternal pattern of inheritance (62,63). One approach aiming to identify sources of heterogeneity in the familial transmission of migraine has been the investigation of vulnerability markers in the relatives of migraine probands. Indeed, alterations in sensory and cognitive-evoked potentials (64-66) as well as hypersensitivity to aversive stimuli (60) have been reported to aggregate in the families of people who have migraine and have been suggested to represent an index of vulnerability to migraine. However, none of these studies tried to evaluate the specificity of these findings in relation to anxiety and mood disorders which have been shown to co-occur in individuals from families with migraine.

Although a comorbidity of migraine with mood and anxiety disorders is well-established (67), there is a lack of prospective research focusing on specific subtypes of these conditions and on their patterns of onset in relation to migraine. In young adults, the onset of anxiety disorders tends to precede that of migraine and to be followed by the onset of depression (68). In order to examine this question prospectively, the offspring of parents with these conditions have been examined in order to identify vulnerability factors and early forms of expression of the anxiety disorders and migraine. The offspring of parents with anxiety disorders were found to display increased startle responsiveness (69,70). This finding indicates that in addition to the possible trigeminal hyperresponsiveness resulting from repeated intense nociceptive stimulation during migraine attacks (54,58), migraine may also be associated with greater responsivity to aversive stimuli, as here reflected in the acoustic startle reflex. The finding of increased reactivity among children who have not yet developed migraine suggests that increased physiological reactivity may be an index of vulnerability to migraine.

These findings support previous studies that documented an increased responsivity to visual, acoustic, somatosensory and nociceptive stimuli in migraineurs (71-73) and strengthens the hypothesis of crossmodal hypersensitivity in migraine.

Since the core neural pathway underlying the acoustic startle reflex is formed by cochlear nuclei (74), startle reflex hypersensitivity could be present at brain stem level or be caused by a top-down modulation. One possible neurobiological mechanism for a top-down modulation could be related to altered central serotonergic transmission. The central serotonergic system is known to modulate acoustic startle (75,76), and altered serotonergic function is believed to be responsible for some of the electrophysiological abnormalities observed in migraine (77).

The startle reflex is also very sensitive to fear and anxiety. In Wang’s study (77), startle was potentiated by fear in the threat condition. Baseline startle reactivity is also increased by contextual threat (e.g., participation in an experiment in which aversive stimuli are anticipated) (78). It is therefore possible that the increased intertrial interval (ITI) startle was caused by anticipatory anxiety, suggesting increased sensitivity to contextual threat in children of migraineurs compared to those of non-migraineurs. Similar results have been reported in children of parents with an anxiety disorder (70). In addition to increased ITI startle, Duncko’s analysis revealed that children at risk of migraine had “higher responses during the threat condition and the threat-safe difference” (79). These findings seem to point to the existence of an impairment of both the “anxiety system” and the “fear system” in the children of migraineurs (78-80).

The significant effect of both maternal anxiety and maternal migraine on ITI startle was shown by Grillon et al. (69,70), and indicates that these two diagnostic entities might in part share common pathophysiological mechanisms. Although maternal inheritance of migraine has been reported in several studies (62,63,81,82), the evidence is inconclusive. Maternal inheritance could be attributable to mitochondrial transmission, pre- or perinatal complications and/or endocrine factors, or a lower threshold for the expression of migraine among women (68). The strong predictive value of maternal history of migraine on startle observed in this study might indicate that increased startle responsiveness is one of several vulnerability factors involved in the pathogenesis of migraine (79).

The significant interaction observed between a maternal history of anxiety and age of offspring showing increased ITI startle responsiveness was attributed to increased amplitude of the startle response in older youth (Grillon et al., unpublished data), a finding consistent with the results of a parallel study that demonstrated an increased potentiated startle after puberty (Grillon et al., unpublished data). This finding might be related to the behavioural sensitisation observed in puberty (83), and might represent a marker of vulnerability to the development of anxiety disorder. No significant association was found between maternal history of anxiety and “startle during the threat condition or the threat-safe difference”, suggesting that children at risk of anxiety exhibit impairment in the “anxiety” but not in the “fear system” (79). In another study (84), although the lack of an association between lifetime migraine and baseline startle among the children investigated was an unexpected finding (see 52-55), it can probably be attributed to the fact that a large proportion of the sample had not yet progressed through the period of risk for migraine (84).

These results are consistent with the current understanding of migraine as a genetically complex disorder (85) and suggest that, in combination with other tests, the startle paradigm could be used as a marker of vulnerability to the onset of migraine. Duncko’s study (79) reports higher acoustic startle responsiveness in children at high risk of developing migraine and anxiety disorder, and thus highlights the importance of assessing migraine and anxiety comorbidity when investigating the pathophysiology of these disorders, since acoustic startle may be a possible marker of vulnerability to developing them.

As regards temperament, the interest of authors has focused particularly on reactivity as one aspect of temperament. According to Zimmermann and Stansbury (86), reactivity (i.e. threshold and intensity of emotional experience) and regulation of emotions (i.e. the control or modulation of this reactivity) are two dimensions of temperament that interact to become behavioural patterns and that can create different developmental trajectories for the child’s personality and life. According to Rothbart (87), the neonatal temperament is defined by individual differences in motor and emotional reactivity, and the “attention ability to support the auto-regulation.”

Recent studies report that early negative emotionality may be a sign of heightened sensitivity or an amplification of bodily reactions to inner and outer stimuli; moreover, it could be a factor related to the development of psychosomatic problems, in particular recurrent headache and abdominal pain.

Studies of visual and auditory evoked potentials and event-related responses have suggested that lack of habituation is the main abnormality of sensory processing in migraneurs. It also seems that the children of migraneurs are more “stress-reactive” than others, having lower physiological reaction thresholds.

One study, assessing the incidence of primary headache and of some components of PS (recurrent abdominal pain, cyclical vomiting, benign paroxysmal vertigo and growing pains) in hyperreactive newborns, found after an 18-year follow up that these newborns suffered from migraine and PS (mainly recurrent abdominal pain) more frequently than the control group (p<0.001) (88).

 

 

Hormones and migraine

 

Epidemiological studies confirm the clinical impression that migraine is mainly a disorder affecting women. Although no gender difference is apparent before puberty, with migraine occurring equally in boys and girls (89), in adults it occurs more frequently in women (18%) than in men (6%) (89). This difference between the sexes becomes greater with age, peaking early in the fifth decade of life and then declining thereafter (89).

Cyclical ovarian sex steroid production may affect the clinical expression of migraine, as demonstrated by a wide variety of clinical, epidemiological, and basic science observations. Clinical observations include the fact that migraine attacks in some women correlate with the menstrual cycle and improve when hormonal cycling ceases during pregnancy or after the menopause. Epidemiological evidence includes the fact that migraine is more common in women than in men, with incidence peaking in the year of menarche.

It is important to distinguish between menstrually-related migraine (MM), premenstrual syndrome (PMS) and attacks that occur mostly at the time of menstruation in women who also have attacks at other times of the cycle.

Somerville (90) did several studies in a small group of women who had a history of pure menstrual migraine in the preceding six menstrual cycles. He noted that oestrogen “priming”, i.e. several days of exposure to high oestrogen concentrations, is necessary in order for migraine attacks to result from oestrogen withdrawal, such as that which occurs in the late luteal phase of the menstrual cycle. This effect would explain why migraine attacks are not associated with ovulation (91). Several other studies support Somerville’s oestrogen withdrawal theory and conclude that changing hormonal activity might be an important factor in all women with migraine; other factors in addition to the hormonal environment could account for the development of menstrual attacks (89). In contrast to the association between oestrogen withdrawal and attacks of migraine without aura, high plasma concentrations of oestrogen seem to be associated with attacks of migraine with aura (92). High oestrogen levels have also been reported in women with migraine with aura during the normal menstrual cycle.

Whether women diagnosed with migraine with aura also had attacks without aura was not clear. Whereas the use of combined oral contraceptives commonly improves migraine without aura, by contrast, migraine with aura becomes worse, or attacks with aura occur for the first time. Granella et al. (93) found that worsening of migraine was more likely to occur with use of combined oral contraceptives in women with pre-existing migraine with aura. These women were also more likely to continue having attacks during pregnancy. Women with pre-existing migraine without aura may develop aura for the first time during pregnancy. Oestrogen concentrations fluctuate throughout the menstrual cycle, showing large interindividual and intraindividual variations in serum concentration and exposing susceptible women to this additional migraine trigger. Ovarian hormones could potentially modulate these structures/pathways to increase or decrease the frequency, severity or duration of migraine headache. While ovarian hormones could potentially affect numerous loci within the trigeminal vascular pain pathways, it is their effect on the trigeminal nucleus caudalis (TNC) that has been best studied. Modulation of neurotransmission within the TNC by ovarian hormones could play an important role in the pathophysiology of migraine headache. Progesterone may also affect neurotransmission within the TNC as well as decrease plasma extravasations in an animal model of migraine headache. The predominant effect of oestrogen appears to be facilitation of the glutamatergic and serotonergic systems as well as inhibition of the sympathetic nervous system. It has both facilitory and inhibitory effects on the opiatergic, GABAergic and noradrenergic systems. The main effect of progesterone and/or its metabolites seems to be activation of GABAergic systems as well as modulation of the actions of oestrogen on the CNS. In addition, oestrogen and progesterone influence the pain processing networks and vascular endothelium, which are believed to be involved in the pathophysiology of migraine headache.

Migraine may worsen during the first trimester of pregnancy and although many women become headache-free during the last two trimesters, 25% experience no change in their migraine. MM typically improves with pregnancy, perhaps due to sustained high oestrogen levels. Hormone replacement therapy with oestrogens can exacerbate migraine and oral contraceptives can change its character and frequency (89). On the basis of quasi-experimental observations in a small number of women with menstrually triggered migraine, Somerville (90) proposed that the late luteal phase drop in oestrogen levels could trigger migraine. A study by Lichten et al. (94) supports oestrogen withdrawal as a migraine trigger in postmenopausal women. However, women with migraine who had undergone surgical menopause had a much less favourable course and the authors concluded that abrupt surgical menopause appeared to worsen migraine. In line with the view that oestrogen withdrawal is an important headache trigger, the majority of women with hormonally influenced migraine report significant headache improvement after the menopause. Although one might expect oestrogen levels in premenopausal women to decline smoothly and gradually during this transition phase, oestradiol levels are in fact increased during the perimenopause, and are often higher than those of the premenstrual years. These factors probably explain the amply documented worsening of headaches during the perimenopausal transition, and the fact that the women in most headache clinics and clinical trials are, on average, in their early 40s. Oestrogen levels decline markedly in the first year after the last menstrual period and then remain low and stable. The oestrogen withdrawal theory of migraine suggests that women may be vulnerable to an exacerbation of their migraine in the perimenopausal years, when the orderly cycling of oestrogen and progesterone secretion becomes more erratic, but that physiological menopause, once it is established, is likely to result in an improvement in migraine. Unfortunately, many studies of headache and migraine in the menopause actually include both perimenopausal and postmenopausal women. There are no reports of women without migraine experiencing migraine headache during oestrogen withdrawal. The most plausible explanation for oestrogen withdrawal as a trigger for migraine is the hypothesis put forward by Welch et al. of a “mismatch” between the timing of oestrogen’s effects on gene regulation in the CNS and its effects on cell membranes (95). He suggests that under ordinary circumstances oestrogen-mediated gene regulation “modulates inhibitory peptide function in the trigeminal nerve.” This counterbalances oestrogen-mediated increases in neuronal membrane excitability. When oestrogen levels fall, their down-regulating effect on inflammatory genes is removed and compensatory mechanisms cannot always be invoked quickly enough to avoid the possibility of headache in women who have “the neuronal excitability that is an inherent feature of the migraine-prone brain.” It is thus not surprising that some women with migraine are particularly vulnerable to attacks during the late luteal phase of the natural menstrual cycle, the pill-free week of combined hormonal contraceptive regimens, or the perimenopause, to name just a few situations that may be characterised by periods of oestrogen decline after sustained high levels.

 

 

Comorbidity

 

Migraine reduces quality of life; part of the burden of migraine is produced by the psychiatric conditions that are associated with it. When one disorder occurs with another with greater-than-chance frequency, the disorders are said to be comorbid. Studies in both clinic and community-based settings have demonstrated an association between migraine and a number of specific psychiatric disorders. While the association between migraine and depression is most widely reported, there are also strong associations with other psychiatric disorders. Understanding the nature of the association between migraine and these psychiatric disorders has implications for diagnosis and treatment. The occurrence of comorbidity may also provide clues as to the aetiology of each disorder. Merikangas et al. (61) studied the association between psychiatric syndromes, including depression, and migraine headache. Migraine was found to be strongly associated with major depression. This (61) was the first study to demonstrate a strong association between migraine and major depression in an unselected sample. Breslau et al. (96) conducted a population-based study of people aged 25 to 55 years with migraine or other severe headaches to examine the relationship between migraine and major depression. This study used Cox proportional hazards models to estimate the risk of first occurrence of migraine associated with prior major depression and the risk of depression associated with prior migraine. Migraine was found to be strongly associated with major depression.

There is a considerable overlap between migraine and depression incidence, and both conditions may be associated with low levels of 5-hydroxytryptamine (5-HT). During a migraine attack there is evidence of low levels of platelet 5-HT and possibly also low Vmax for 5-HT uptake; these two findings are also associated with the depressed state. Both conditions can be treated by tricyclic and monoamine oxidase-inhibiting antidepressants. Migraine may form part of a family of brief recurrent self-limiting disorders, which involve disturbances of both mood and monoamines; during the “headache phase of the migraine attack, the links with depression are most apparent” (97).

Breslau suggests the existence of a “bi-directional” influence between migraine and depression, with each disorder increasing the risk of first onset of the other (98).

Unfortunately we do not know of any studies exploring the relationship between migraine and depression after the menopause. With regard to the comorbidity of menopause and depression, we can say woman more often suffer from depression than men, particularly in the perimenopausal stage, indicating that low oestrogen levels might be involved in the aetiology of this disease. Several studies have supported this hypothesis (1,99). On the other hand, other studies found no correlation between menopause and depression (100-102).

In a prospective, population-based study, Swartz et al. (103) examined the relationship between specific psychiatric disorders and migraine. In cross-sectional analyses, major depression was found to be strongly associated with migraine.

These results, in combination with those reported by Breslau et al. in 2000 (96), suggest that the bidirectional relationship is specific to migraine, and does not extend to all severe headaches. Anxiety disorders are also associated with migraine. This relationship has been observed in both clinic and community-based populations. These two studies have demonstrated a cross-sectional relationship between migraine and various anxiety disorders.

Breslau’s study (96) reported that the association between migraine and anxiety disorders was even stronger than that for other affective disorders. Although phobias were generally associated with migraine, agoraphobia did not show this relationship, a fact that may be explained by the rarity of this condition. An association between migraine and panic disorder has also been reported, but the temporal relationship between the two disorders has not been thoroughly explored.

Many studies indicate that panic disorder is comorbid not only with migraine, but also with other headache types. Investigation of the temporal relationship between these disorders suggests that the influence is exerted in the headache-to-panic disorder direction, rather than the reverse.

Merikangas et al. (61) also reported the results of a logistic regression analysis conducted to examine the diagnostic overlap between the psychiatric disorders most strongly associated with migraine. The model controlled for sex and risk group while assessing the effects of major depression, bipolar spectrum, general anxiety disorder, and social phobia. The best fitting model included only general anxiety disorder. Migraine and anxiety disorders are comorbid conditions and in some studies, the relationship is even stronger than that between migraine and depression.

In addition, most people with depression also have anxiety disorders, but many people with anxiety disorders do not have depression. For this reason, it is important to screen for both depression and anxiety in individuals with migraine. Several studies (104,105) have reported high levels of depression, anxiety and somatisation symptoms in children and adolescents with migraine. The results of a prospective longitudinal cohort study of young adults revealed that the onset of anxiety disorders tended to precede that of migraine in about 80% of the cases of migraine with comorbid anxiety and depression, and that the onset of depression followed that of migraine in 75% of the comorbid cases (68). LeResche (106) found that significant levels of depression were roughly twice as frequent in boys and more than four times as frequent in girls who had already gone through puberty compared with those who had not begun pubertal development. These results are similar to those of a recent large cross-sectional study (107) which found an association between a trichomised measure of pubertal development and physical symptoms, including headache. In a study of adolescents girls, Sillanpää and Aro (108) found a higher frequency of headache and depression among those with a younger age at menarche.

 

 

Environmental risk

 

Aromää and coworkers (105) investigated the predictors of headache in children at school entry. Frequent headache in the mother prior to pregnancy was found to be strongly predictive of headache in the child before school entry. The mother’s assessment of her infant’s poor health status and feeding problems at the age of 9 months was significantly predictive of preschool headache. Nocturnal confusion seizures and suspected headache in the child or in his or her family members at the follow up at the age of 3 years were significantly associated with later headache in the child. At the same age, the presence of recurrent difficulties in falling asleep was also predictive of later headache. At 5 years of age, the presence of long-term disease, nocturnal enuresis, and travel sickness were headache predictors. Headache occurring in attacks and tension headache were predictive of headache at school entry.

As regards psychological factors, concentration difficulties, behavioural problems, and unusual tiredness at the age of 5 years were strong predictors of headache. High sociability was also predictive; instead, up to the age of 5 years, parents’ divorce, being in a one-parent family, and number of siblings were not predictive of headache occurring before school age, nor were several relocations, hours of television watching, or other parenthood variables.

Messinger et al. (109) found that the prevalence of headache sufferers rose from 64% when neither parent was a headache sufferer to 85% when one parent had headache episodes and to 98% when both parents reported headache episodes. In that study, the “heredity” of headache was also recognisable; again, it was observed that having a mother with frequent prepregnancy headache was strongly predictive of headache at preschool age.

In addition (62), a history of maternal depression occurred 1.5 times more often in headache and migraine groups than in controls. The mother’s assessment of her infant’s poor health at 9 months was predictive of preschool headache. The mother’s tendency towards depression and her sensitivity to the somatic complaints of her infant are aspects worthy of consideration (62).

Merikangas et al. (61) found that migraine combined with anxiety and depression may constitute a distinct clinical syndrome, often manifesting in early childhood. Conversely, some “positive characteristics” in a child can be predictive of headache, for example high sociability at the age of 5 years has been found to be a strong predictor of headache. In a study by Borge and Nordhagen (110), children complaining of headache showed good conduct as preschoolers and a tendency towards high achievement motivation at school. This tendency may explain their sociability, although their efforts to excel may cause exhaustion and tiredness leading to concentration difficulties. When relations between predictor variables were analysed in this study (110), an association emerged between high sociability and concentration difficulties. Such analyses have helped to clarify the profile of child headache sufferers and their families. The presence of concentration difficulties seems to be a very strong predictor of headache.

A number of other studies (e.g. 111-113) have also reported a relationship between low socioeconomic status and pain in children and/or adolescents. However, there are also studies in which no such relationship was found (e.g. 114,115). If low social class is a risk indicator for pain in adolescents, a number of possible mechanisms (e.g. levels of family and economic stress, living conditions, patterns of health care utilisation) might be involved. This finding suggests that biological development (over and above growing older, i.e. the simple passage of time, and age-related exposures) plays an important role in this adolescent population.

LeReche et al. (106) confirm that the prevalence of pain conditions in adolescents, particularly adolescent girls, is substantial. In addition, we have found that physical development as well as gender is associated with the experience of pain in adolescents. These findings suggest that the process of pubertal development may initiate biological changes that predispose women, in particular, to experience symptoms, including pain (106).

 

 

Gender differences, prevalence and pain perception

 

Although chronic/recurrent pain is generally considered a problem of adults, the rates of some pain conditions – particularly back pain and headache – are substantial in adolescents, ranging from 20 to 50% of the teenage population (116-118). Moreover, many adults with persistent pain report that their pain condition had onset during adolescence.

Many epidemiological studies of pain in adolescents consider age as a risk factor. However, few (104,107, 119,120) have examined the relationship of pain to pubertal development. The sequence of hormonal and anatomical changes occurring during puberty is similar in individuals of a given sex, but the age at onset of puberty and rates of change can vary widely. At a given age, adolescents of the same sex may be in very different stages of puberty, with some yet to begin pubertal development and others who have completed it. Thus, while older adolescents are generally further along in pubertal development than younger ones, age is not a robust indicator of biological/hormonal status in adolescents. In addition to the physical changes associated with puberty, adolescence is a time of rapid cognitive and social development (121). Although the stereotype of adolescence as a turbulent and emotionally troubled period is an exaggeration, some adolescents do experience great emotional distress (122). In adults, psychological distress, notably depression (123), is commonly associated with chronic pain conditions. Depression is more likely among persons with multiple pain conditions as opposed to a single pain condition (124). In addition, the presence of multiple pain conditions may predict onset (125) and persistence (126,127) of chronic pain in other body sites.

LeResche et al. (106) hypothesised that the prevalence of all pain conditions, as well as rates of other symptoms, increases with the progression of puberty in females, but not males. In both sexes, pubertal development was found to be a better predictor of pain than age, and it was found that pain, other somatic symptoms and depression increase systematically with pubertal development in girls. Accordingly, the prevalence of headache pain was similar for boys at all stages of puberty, the prevalence of back pain and facial pain increased with increasing levels of pubertal development, and the prevalence of stomach pain declined as boys became more mature. In girls, the prevalence of each pain condition increased with increasing levels of pubertal development, although the increase in stomach pain was not statistically significant. In both boys and girls, the probability of experiencing at least one pain condition and of experiencing two or more pain conditions increased with increasing physical maturity.

Because this was a cross-sectional study, it is not possible to determine cause and effect relationships between the variables measured. However, it appears more logical to assume that pubertal status influences the rates of pain and symptoms than to infer that the presence of pain and symptoms alters rates of pubertal development.

Angold et al.’s findings of dramatic increases in depression with pubertal development in girls (128) are similar to those of longitudinal studies. Because both psychological distress and pain prevalence are associated with pubertal status, especially in girls, depression and somatic symptoms added little to the prediction of pain in multivariate models.

Children with recurrent headaches have a risk of developing additional physical and mental problems, such as anxiety and depression, in adulthood. In addition, recurrent abdominal pain among children and adolescents not only affects physical and psychosocial aspects of daily family life but may also predispose children to experience recurrent pain-related illnesses in adulthood. Most studies evaluating recurrent or chronic pain conditions in children have been limited to descriptions of pain intensity and duration. The effects of pain states and their impact on daily living have rarely been studied. The objective of one study, conducted in an elementary school and in two secondary schools in Germany by Roth-Isigkeit (129), was to investigate the impact of perceived pain on the daily lives and activities of children and adolescents. More than two thirds of the respondents reported restrictions in daily living activities attributable to pain. However, 30 to 40% of children and adolescents with pain reported moderate effects of their pain on school attendance, participation in hobbies, maintenance of social contacts, appetite, and sleep, as well as increased utilisation of health services because of their pain. Restrictions in daily activities in general and health care utilisation because of pain both increased with age. Girls ≥ 10 years of age reported more restrictions in daily living and used more medications for their pain than did boys of the same age. The authors found gender-specific differences in self-perceived triggers of pain. Boys more often than girls stated that their pain was triggered by physical exertion. Girls more often than boys stated that their pain was triggered by weather conditions, common colds, or internal factors such as anger, disputes, family conditions, or sadness. Previous studies confirmed the roles of school or everyday stress, examinations, and the overall school experience in the prevalence of paediatric headache. Psychosocial aspects (e.g. positive friendships and supportive relationships with parents or other adults) were indicated to influence the prevalence and severity of back pain among adolescents. Pain intensity was the most robust variable for predicting functional impairment in ≥ 1 areas of daily life. Increasing age of the child and increasing intensity and duration of pain had effects in predicting health care utilisation (visiting a doctor and/or taking medication), whereas restrictions in daily activities were predicted only by the intensity of pain. These results underscore the importance of paediatric pain for public health policy making. Additional studies are necessary and may enhance our knowledge about paediatric pain. This, in turn, might enable parents, teachers, and health care professionals to assist young people with pain management, allowing them to intervene positively in their conditions before they become recurrent or persistent (129).

 

 

Concluding remarks

 

Migraine and affective disorders can be present in the same subject. This seems to be particularly true of girls and women. The aim of this paper was to analyse the different factors (medical vs psychological) that can, partially, explain this association.

Many questions remain unanswered.

Future epidemiological studies should be done to analyse migraine in postmenopausal women. Researchers should develop methods of tracking individuals from childhood through adulthood to assess the prevalence and natural history of this disorder. The influence of genetics, family environment, social learning, behaviour, and psychological comorbidities needs to be established. Furthermore, there is a need to develop and evaluate educational and counselling programmes targeting both children with migraine and their families.

A better understanding of the evolution and comorbidities of migraine in children may lead to improved clinical outcomes as they become adults.

 

 

References

 

1.         Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and   menopausal status as predictors of depression in women in transition to menopause. Arch Gen Pychiatry 2004;61:62-70

2.         Loder E, Rizzoli P, Golub J. Hormonal management of migraine associated with menses and the menopause: a clinical review”. Headache 2007;47:329-340

3.         Minuchin S, Baker L, Rosman BL, Liebman R, Milman L, Todd TC. A conceptual model of psychosomatic illness in children: Family organization and family therapy. Arch Gen Psychiatry 1975;32:1031-1038

4.         Byng-Hall J. Symptom bearer as distance regulator: clinical implications. Fam Process 1980;19:355-365

5.         Onnis L, Tortolani D, Cancrini L. Systemic research on chronicity factors in infantile asthma. Fam Process 1986; 25:107-121

6.         Wood B, Watkins JB, Boyle JT, Nogueira J, Zimand E, Carroll L. The “psychosomatic family” model: an empirical and theoretical analysis. Fam Process 1989;28:399-417

7.         Northey S, William AG, Krainz S. A partial test of the psychosomatic family model: marital interaction on patterns in asthma and non-asthma families. Journal of Family Psychology 1998;12:220-233

8.         Wirsching M, Stierlin H. Psychosomatics I: psychosocial characteristics of psychosomatic patients and their families. Family Systems Medicine 1985;3:6-17

9.         Weakland J. Family somatics – a neglected edge. Fam Process 1977;16:263-273

10.       Guidetti V, Galli F, Cerutti R, Fortugno S. “From 0 to 18”: what happens to the child and his headache? Funct Neurol 2000;15(Suppl 3):122-129

11.       Bener A, Uduman SA, Qassimi EM et al. Genetic and environmental factors associated with migraine in schoolchildren. Headache 2000;40:152-157

12.       Ochs M, Seemann M, Franck G, Wredenhagen N, Verres R, Schweitzer J. Primary headache in children and adolescents: therapy outcome and changes in family interaction patterns. Families, Systems, & Health 2005;23:30-53

13.       Laplante DP, Barr RG, Brunet A et al. Stress during pregnancy affects general intellectual and language functioning in human toddlers. Pediatr Res 2004;56:400-410

14.       Weinstock M. Does prenatal stress impair coping and regulation of the hypothalamic-pituitary- adrenal axis? Neurosci Biobehav Rev 1997;21:1-10

15.       Clarke AS, Wittwer DJ, Abbott DH, Schneider ML. Long-term effects of prenatal stress on HPA axis activity in juvenile rhesus monkeys. Dev Psychobiol 1994;27:257-269

16.       Davis EP, Snidman N, Wadhwa PD, Glynn L, Dunkel-Schetter C, Sandman CA. Prenatal maternal anxiety and depression predict negative behavioral reactivity in infancy. Infancy 2004;6:319-331

17.       Schneider ML. Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants. Dev Psychobiol 1992;25: 529-540

18.       O’Connor TG, Heron J, Golding J, Glover V; ALSPAC Study Team. Maternal antenatal anxiety and behavioural/ emotional problems in children: A test of a programming hypothesis. J Child Psychol Psychiatry 2003;44:1025-1036

19.       Van den Bergh BR, Marcoen A. High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems and anxiety in 8- and 9-year-olds. Child Dev 2004; 75:1085-1097

20.       Weinstock M. Alterations induced by gestational stress in brain morphology and behavior of the offspring. Prog Neurobiol 2001;65:427-451

21.       Ward AMV, Phillips DJW. Fetal programming of stress responses. Stress 2001;4:263-271

22.       Welberg LA, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001; 13:113-128

23.       Economides D, Linton E, Nicolaides K, Rodeck CH, Lowry PJ, Chard T. Relationship between maternal and fetal corticotropin-releasing hormone-41 and ACTH levels in human mid-trimester pregnancy. J Endocrinol 1987;114:497-501

24.       Gitau R, Fisk NM, Glover V. Human fetal and maternal corticotrophin releasing hormone responses to acute stress. Arch Dis Child Fetal Neonatal Ed 2004;89:F29-F32

25.       Goland RS, Wardlaw SL, Blum M, Tropper PJ, Stark RI. Biologically active corticotropin-releasing hormone in maternal and fetal plasma during pregnancy. Am J Obstet Gynecol 1988;159:884-890

26.       Stalla GK, Bost H, Stalla J et al. Human corticotropin-releasing hormone during pregnancy. Gynecol Endocrinol 1989;3:1-10

27.       King BR, Smith R, Nicholson RC. The regulation of human corticotropin-releasing hormone gene expression in the placenta. Peptides 2001;22:795-801

28.       Avishai-Eliner S, Brunson KL, Sandman CA, Baram TZ. Stressed-out, or in (utero)? Trends Neurosci 2002;25: 518-524

29.       Sandman CA, Wadhwa PD, Chicz-DeMet A, Porto M, Garite TJ. Maternal corticotropin-releasing hormone and habituation in the human fetus. Dev Psychobiol 1999;34: 163-173

30.       Mastorakos G, Ilias I. Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann NY Acad Sci 2003;997:136-149

31.       Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP. Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 1999;180:S257-S263

32.       Holzman C, Jetton J, Siler-Khodr T, Fisher R, Rip T. Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity. Obstet Gynecol 2001;97:657-663

33.       McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy. Nat Med 1995;1:460-463

34.       Wadhwa PD, Porto M, Garite TJ, Chicz-DeMet A, Sandman CA. Maternal corticotrophin-releasing hormone levels in the third trimester predict length of gestation in human pregnancy. Am J Obstet Gynecol 1998;179:1079-1085

35.       Wadhwa PD, Garite TJ, Porto M et al. Placental corticotropin-releasing hormone (CRH), spontaneus preterm birth, and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol 2004;191:1063-1069

36.       Sandman CA, Wadhwa PD, Chicz-DeMet A, Porto M, Garite TJ. Maternal corticotropin-releasing hormone and habituation in the human fetus. Dev Psychobiol 1999;34: 163-173

37.       Denver RJ. Environmental stress as a developmental cue: corticotropin-releasing hormone is a proximate mediator of adaptive phenotypic plasticity in amphibian metamorphosis. Horm Behav 1997;31:169-179

38.       Davis EP, Glynn LM, Dunkel-Schetter C, Hobel C, Chicz-Demet A, Sandman C. Corticotropin-releasing hormone during pregnancy is associated with infant temperament. Dev Neurosci 2005;27:299-305

39.       Williams MT, Hennessy MB, Davis HN. CRF administered to pregnant rats alters offspring behavior and morphology. Pharmacol Biochem Behav 1995;52:161-167

40.       DiPietro JA. The role of prenatal maternal stress in child development. Current Directions in Psychological Science 2004;13:71-74

41.       Susman EJ, Schmeelk KH, Ponirakis A, Gariepy JL. Maternal prenatal, postpartum, and concurrent stressors and temperament in 3-year-olds: a person and variable analysis. Dev Psychopathol 2001;13:629-652

42.       Huizink AC, de Medina PG, Mulder EJ, Visser GH, Buitelaar JK. Psychological measures of prenatal stress as predictors of infant temperament. J Am Acad Child Adolesc Psychiatry 2002;41:1078-1085

43.       Graham YP, Heim C, Goodman SH, Miller AH, Nemeroff CB. The effects of neonatal stress on brain development: implications for psychopathology. Dev Psychopathol 1999; 11:545-565

44.       de Weerth C, Van Hees Y, Buitelaar JK. Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Hum Dev 2003;74:139-151

45.       Sweet SD, MacGrath PJ, Symons D. The roles of child reactivity and parenting context in infant pain response. Pain 1999;80:655-661

46.       Field T, Pickens J, Fox NA, Nawrocki T, Gonzales J. Vagal tone in infants of depressed mothers. Development and Psychopathology 1995;7:227-231

47.       Izard CE, Porges SW, Simons RF, Haynes OM, Parisi M, Cohen B. Infant cardiac activity: developmental changes and relations with attachment. Developmental Psychology 1991;27:432-439

48.       Lee LW, White-Traut RC. The role of temperament in pediatric pain response. Issues Compr Pediatr Nurs 1996;19: 49-63

49.       Schechter NL, Bernstein BA, Beck A, Hart L, Scherzer L. Individual differences in children’s response to pain: role of temperament and parental characteristics. Pediatrics 1991;87:171-177

50.       Davison JS, Faull C, Nicol AR. Research note: temperament and behavior in six-year-olds with recurrent abdominal pain: a follow up. J Child Psychol Psychiatry 1986;27: 539-544

51.       Guidetti V, Ottaviano S, Pagliarini M. Childhood headache risk: warning signs and symptoms present during the first six month of life. Cephalalgia 1984;4:237-242

52.       Katsarava Z, Giffin N, Diener HC, Kaube H. Abnormal habituation of ‘nociceptive’ blink reflex in migraine – evidence for increased excitability of trigeminal nociception. Cephalalgia 2003;23:814-819

53.       Sandrini G, Proietti Cecchini A, Milanov I, Tassorelli C, Buzzi MG, Nappi G. Electrophysiological evidence for trigeminal neuron sensitization in patients with migraine. Neurosci Lett 2002;317:135-138

54.       Weissman-Fogel I, Sprecher E, Granovsky Y, Yarnitsky D. Repeated noxious stimulation of the skin enhances cutaneous pain perception of migraine patients in-between attacks: clinical evidence for continuous sub-threshold increase in membrane excitability of central trigeminovascular neurons. Pain 2003;104:693-700

55.       Zohsel K, Hohmeister J, Oelkers-Ax R, Flor H, Hermann C. Quantitative sensory testing in children with migraine: preliminary evidence for enhanced sensitivity to painful stimuli especially in girls. Pain 2006;123:10-18

56.       Gantenbein AR, Sándor PS. Physiological parameters as biomarkers of migraine. Headache 2006;46:1069-1074

57.       Schoenen J, Ambrosini A, Sándor PS, Maertens de Noordhout A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin Neurophysiol 2003; 114:955-972

58.       Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614-624

59.       Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-1769

60.       Di Clemente L, Coppola G, Magis D et al. Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine? Brain 2007; 130:765-770

61.       Merikangas KR, Fenton B. Comorbidity of migraine with medical disorders. Seminars in Headache Management 1996;1:3-6

62.       Mortimer MJ, Kay J, Jaron A, Good PA. Does a history of maternal migraine or depression predispose children to headache and stomach-ache? Headache 1992;32:353-355

63.       Wang Q, Ito M, Adams K et al. Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome. Am J Med Genet A 2004;131:50-58

64.       Sándor PS, Afra J, Proietti Cecchini A, Albert A, Schoenen J. Familial influences on cortical evoked potentials in migraine. Neuroreport 1999;10:1235-1238

65.       Siniatchkin M, Kirsch E, Kropp P, Stephani U, Gerber WD. Slow cortical potentials in migraine families. Cephalalgia 2000;20:881-992

66.       Siniatchkin M, Kropp P, Gerber WD. Contingent negative variation in subjects at risk for migraine without aura. Pain 2001;94:159-167

67.       Radat F, Swendsen J. Psychiatric comorbidity in migraine: a review. Cephalalgia 2005;25:165-178

68.       Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Results of the Zurich cohort study of young adults. Arch Gen Psychiatry 1990;47:849-853

69.       Grillon C, Dierker L, Merikangas KR. Startle modulation in children at risk for anxiety disorders and/or alcoholism. J Am Acad Child Adolesc Psychiatry 1997;36:925-932

70.       Grillon C, Ameli R. Effects of threat and safety signals on startle during anticipation of aversive shocks, sounds, and airblasts. Journal of Psychophysiology 1998;12:329-337

71.       Afra J, Proietti Cecchini A, Sándor PS, Schoenen J. Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks. Clin Neurophysiol 2000; 111:1124-112972.       Katsarava Z, Giffin N, Diener HC, Kaube H. Abnormal habituation of ‘nociceptive’ blink reflex in migraine – evidence for increased excitability of trigeminal nociception. Cephalalgia 2003;23:814-819

73.       Lang E, Kaltenhäuser M, Neundörfer B, Seidler S. Hyperexcitability of the primary somatosensory cortex in migraine – a magnetoencephalographic study. Brain 2004; 127:2459-2469

74.       Yeomans JS, Li L, Scott BW, Frankland PW. Tactile, acoustic and vestibular systems sum to elicit the startle reflex. Neurosci Biobehav Rev 2002;26:1-11

75.       Liechti ME, Geyer MA, Hell D, Vollenweider FX. Effects of MDMA (ecstasy) on prepulse inhibition and habituation of startle in humans after pretreatment with citalopram, haloperidol, or ketanserin. Neuropsychopharmacology 2001;24:240-252

76.       Quednow BB, Kühn KU, Hoenig K, Maier W, Wagner M. Prepulse inhibition and habituation of acoustic startle response in male MDMA (‘ecstasy’) users, cannabis users, and healthy controls. Neuropsychopharmacology 2004;29: 982-990

77.       Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404-1409

78.       Grillon C, Baas J. A review of the modulation of the startle reflex by affective states and its application in psychiatry. Clin Neurophysiol 2003;114:1557-1579

79.       Duncko R, Cui L, Hille J, Grillon C, Merikangas KR. Startle reactivity in children at risk for migraine. Clin Neurophysiol 2008;119:2733-237

80.       Walker DL, Toufexis DJ, Davis M. Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 2003;463:199-216

81.       Baier WK. Genetics of migraine and migraine accompagnée: a study of eighty-one children and their families. Neuropediatrics 1985;16:84-91

82.       Dalsgaard-Nielsen T. Migraine and heredity. Acta Neurol Scand 1965;41:287-300

83.       Rudolph KD, Flynn M. Childhood adversity and youth depression: influence of gender and pubertal status. Dev Psychopathol 2007;19:497-521

84.       Rasmussen BK. Migraine and tension-type headache in a general population: precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain 1993; 53:65-72

85.       Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA. Migraine: a complex genetic disorder. Lancet Neurol 2007;6:521-532

86.       Zimmermann LK, Stansbury K. The influence of emotion regulation, level of shyness, and habituation on the neuroendocrine response of three-year-old children. Psychoneuroendocrinology 2004;29:973-982

87.       Rothbart MK, Ahadi SA, Hershey KL, Fisher P. Investigations of temperament at three to seven years: the Children’s Behavior Questionnaire. Child Dev 2001;72:1394-1408

88.       Marugán JM, Fernández-Castaño MT, del Carmen Torres M, del Carmen de Fuentes M. The functional recurrent abdominal pain (RAP) in children may be the precursor of adult migraine. Cephalalgia 2008;28:571-572

89.       Silberstein SD. Sex hormones and headache. Rev Neurol (Paris) 2000;156(Suppl 4):4S30-4S41

90.       Somerville BW. The role of estradiol withdrawal in the etiology of mestrual migraine. Neurology 1972;22:355-365

91.       Loder E, Rizzoli P, Golub J. Hormonal management of migraine associated with menses and the menopause: a clinical review. Headache 2007;47:329-340

92.       MacGregor EA. Oestrogen and attacks of migraine with and without aura. Lancet Neurol 2004;3:354-361

93.       Granella F, Sances G, Pucci E, Nappi R, Ghiotto N, Nappi G. Migraine with aura and reproductive life events: a case control study. Cephalalgia 2000;20:701-707

94.       Lichten EM, Lichten JB, Whitty A, Pieper D. The confirmation of a biochemical marker for women's hormonal migraine: the depo-estradiol challenge test. Headache 1996; 36:367-371

95.       Welch KM, Brandes JL, Berman NE. Mismatch in how oestrogen modulates molecular and neuronal function may explain menstrual migraine. Neurol Sci 2006;27(Suppl 2): S190-192

96.       Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KM. Headache and major depression: is the association specific to migraine? Neurology 2000;54:308-313

97.       Glover V, Jarman J, Sandler M. Migraine and depression: biological aspects. J Psychiatr Res 1993;27:223-231

98.       Breslau N, Davis GC, Schultz LR, Peterson EL. Migraine and major depression: a longitudinal study. Headache 1994;34:387-393

99.       Maartens LW, Knottneruss JA, Pop VJ. Menopausal transition and increased depressive symptomatology: a community based prospective study. Maturitas 2002;42:195-200

100.     Avis NE, Crawford S, Stellato R, Longcope C. Longitudinal study of hormone levels and depression among woman transitioning through menopause. Climacteric 2001;4:243-249

101.     Brosworth HB, Bastian LA, Kuchibhatla MN et al. Depressive symptoms, menopausal status and climacteric symptoms in woman at midlife. Psychosom Med 2001;63:603-608

102.     Li Y, Yu Q, Ma L, Sun Z, Yang X. Prevalence of depression and anxiety symptoms and their influence factors during menopausal transition and postmenopause in Beijng City. Maturitas 2008;61:238-242

103.     Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW. Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore Epidemiologic Catchment area follow-up study. Arch Gen Psychiatry 2000;57:945-950

104.     Passchier J, Orlebeke JF. Headaches and stress in schoolchildren: an epidemiological study. Cephalalgia 1985;5:167-176

105.     Aromää M, Rautava P, Helenius H, Sillanpää ML. Factors of early life as predictors of headache in children at school entry. Headache 1998;38:23-30

106.     LeResche L, Mancl LA, Drangsholt MT, Saunders K, Korff MV. Relationship of pain and symptoms to pubertal development in adolescents. Pain 2005;118:201-209

107.     Rhee H. Relationships between physical symptoms and pubertal development. J Pediatr Health Care 2005;19:95-103

108.     Sillanpää M, Aro H. Headache in teenagers: comorbidity and prognosis. Funct Neurol 2000;15(Suppl 3):116-121

109.     Messinger HB, Spierings EL, Vincent AJ, Lebbink J. Headache and family history. Cephalalgia 1991;11:13-18

110.     Borge Al, Nordhagen R. Development of stomach-ache and headache during middle childhood: co-occurrence and psychosocial risk factors. Acta Paediat 1995;84:795-802

111.     Antilla P, Metsähonkala L, Mikkelsson M et al. Muscle tenderness in pericranial and neck-shoulder region in children with headache. A controlled study. Cephalalgia 2002; 22:340-344

112.     Grøholt EK, Stigum H, Nordhagen R, Köhler L. Recurrent pain in children, socio-economic factors and accumulation in families. Eur J Epidemiol 2003;18:965-975

113.     Sillanpää M, Piekkala P, Kero P. Prevalence of headache at preschool age in an unselected child population. Cephalalgia 1991;11:239-242

114.     Mikkelsson M, Salminen JJ, Kautiainen H. Non-specific musculoskeletal pain in preadolescents: prevalence and 1-year persistence. Pain 1997;73:29-35

115.     Kristjánsdóttir G, Rhee H. Risk factors of back pain frequency in schoolchildren: a search for explanations to a public health problem. Acta Paediatr 2002;91:849-854

116.     Kristjánsdóttir G. Prevalence of self-reported back pain in school children: a study of sociodemographic differences. Eur J Pediatr 1996;155:984-986 

117.     Gordon KE, Dooley JM, Wood EP. Self-reported headache frequency and features associated with frequent headaches in Canadian young adolescents. Headache 2004;44:555-561

118.     Watson KD, Papageorgiou AC, Jones GT et al. Low back pain in school children: occurrence and characteristics. Pain 2002;97:87-92

119.     Deubner DC. An epidemiologic study of migraine and headache in 10-20 year olds. Headache 1977;17:173-180

120.     Wedderkopp N, Leboeuf-Yde C, Bo Andersen L, Froberg K, Steen Hansen H. Back pain in children: no association with objectively measured level of physical activity. Spine 2003;17:2019-2024

121.     Ingersoll GM. Psychological and social development. In: McAnarney ER, Kreipe RE, Orr DP, Comerci GD eds Textbook of Adolescent Medicine. Philadelphia; W.B. Saunders Co. 1992:91-98

122.     Weiner IB. Normality during adolescence. In: McAnarney ER, Kreipe RE, Orr DP, Comerci GD eds Textbook of Adolescent Medicine. Philadelphia; W.B. Saunders Co. 1992: 86-90

123.     Turner JA, Romano JM. Review of prevalence of coexisting chronic pain and depression. In: Benedetti C, Chapman CR, Moricca G eds Recent Advances in the Management of Pain. New York; Raven Press 1984:123-130

124.     Dworkin SF, Von Korff M, LeResche L. Multiple pains and psychiatric disturbance: an epidemiologic investigation. Arch Gen Psychiatry 1990;47:239-244

125.     Von Korff M, LeResche L, Dworkin SF. First onset of common pain symptoms: a prospective study of depression as a risk factor. Pain 1993;55:251-258

126.     John MT, Miglioretti DL, LeResche L, Von Korff M, Critchlow CW. Widespread pain as a risk factor for dysfunctional temporomandibular disorder pain. Pain 2003; 102:257-263

127.     Rammelsberg P, LeResche L, Dworkin SF, Mancl L. Longitudinal outcome of temporomandibular disorders: a 5-year epidemiologic study of muscle disorders defined by research diagnostic criteria for temporomandibular disorders. J Orofac Pain 2003;17:9-20

128.     Angold A, Costello EJ, Worthman CM. Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychol Med 1998;28:51-61

129.     Roth-Isigkeit A, Thyen U, Stöven H, Schwarzenberger J, Schmucker P. Pain among children and adolescents: restrictions in daily living and triggering factors. Pediatrics 2005;115:e152-e162