Early-life origin of adult insomnia: does prenatal–early-life stress play a role?

Accepted Manuscript Title: Early life origin of adult insomnia: does prenatal-early life stress play a role? Author: Laura Palagini, Christopher L.Drake, Philip Gehrman, Peter Meerlo, Dieter Riemann PII: DOI: Reference:

S1389-9457(15)00027-1 http://dx.doi.org/doi: 10.1016/j.sleep.2014.10.013 SLEEP 2631

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Sleep Medicine

Received date: Revised date: Accepted date:

4-6-2014 28-10-2014 29-10-2014

Please cite this article as: Laura Palagini, Christopher L.Drake, Philip Gehrman, Peter Meerlo, Dieter Riemann, Early life origin of adult insomnia: does prenatal-early life stress play a role?, Sleep Medicine (2015), http://dx.doi.org/doi: 10.1016/j.sleep.2014.10.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title page

Early life origin of adult insomnia: does prenatal-early life stress play a role? 1)Laura Palagini,2) Christopher L.Drake, 3)Philip Gehrman, 4)Peter Meerlo 5) Dieter Riemann

1. Department of Clinical Experimental Medicine, Psychiatric Unit, University of Pisa, School of Medicine, Via Roma 67, 56100, Pisa, Italy 2. Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, MI,USA 3. Department of Psychiatry Perelman School of Medicine at the University of Pennsylvania, USA 4. Department of Molecular Neurobiology, Center for Behavior and Neurosciences, University of Groningen, The Netherlands. 5) Department of Clinical Psychology and Psychophysiology/ Sleep Medicine, Center for Mental Disorders, Freiburg University Medical Centre, Germany.

Corresponding author: Laura Palagini, Department of Clinical Experimental Medicine, Psychiatric Unit, University of Pisa, School of Medicine, Via Roma 67, 56100, Pisa, Italy, +39-050993165, fax: +39-050-992265; email address: [email protected], [email protected]

Running title: early life origin of insomnia Highlights Prenatal-early life stress may results in an activation of the stress system in the newborn It may encompass long-lasting modifications in stress reactivity which may persist into adulthood. It might predispose to a vulnerability to stress related hyperarousal and insomnia into adulthood Page 1 of 32

Epigenetic mechanisms may be involved in shaping stress responses predisposing to insomnia

Abstract Insomnia is very common in the adult population and includes a wide spectrum of sequelae, i.e., neuroendocrine and cardiovascular alterations as well as psychiatric and neurodegenerative disorders. According to the conceptualization of insomnia in the context of the 3P model, the importance of Predisposing, Precipitating, and Perpetuating factors has been stressed. Predisposing factors are present before insomnia is manifested and are hypothesized to interact with precipitating factors, i.e. environmental stressful events, contributing to the onset of insomnia. Understanding the early life origins of insomnia may be particularly useful in order to prevent and treat this costly phenomenon. Based on recent evidence, prenatal early life stress exposure results in a series of responses that involve the stress system in the child and could persist into adulthood. This may encompass an activation of the hypothalamic-pituitary-adrenal axis accompanied by long-lasting modifications in stress reactivity. Furthermore, early life stress exposure might play an important role in predisposing to a vulnerability to hyperarousal reactions to negative life events in the adult contributing to the development of chronic insomnia. Epigenetic mechanisms may also be involved in the development of maladaptive stress responses in the newborn, ultimately predisposing to develop a variety of (psycho-) pathological states in adult life. Key words: prenatal, childhood, stress, epigenetic, adult insomnia

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Introduction Insomnia symptoms are very common, affecting one third of the adult population; insomnia disorder is the most prevalent among the sleep disorders afflicting approximately 6%-10% of adults [1]. Experimental and epidemiological studies conducted in adults show that poor sleep and insomnia have a wide spectrum of sequelae, including neuroendocrine and cardiovascular alterations as well as psychiatric and neurodegenerative disorders [2-9]. From a life course perspective on health, understanding the early life origins of insomnia may be particularly useful in order to prevent and treat this disturbance, which is of high economic relevance for health care systems [10]. In addition, the association of insomnia with new onset depressive disorder suggests the potential for downstream benefits of insomnia treatment with respect to prevention of psychiatric disorders [11,12]. It is the aim of this paper to systematically review the evidence regarding the early-life origin of adult insomnia from prenatal to childhood origin.

Background of the hypothesis -Stress system and predisposition to insomnia: model of insomnia in adult and infant A heuristic model of insomnia is the diathesis-stress model proposed by Spielman et al. [13] commonly known as the “3-P” model. The model describes predisposing, precipitating, and perpetuating factors relevant for the development and maintenance of insomnia. Predisposing factors include genetic, physiological, or psychological diatheses that confer differential susceptibility to individuals. These predisposing factors interact with Precipitating factors such as physiological or environmental stressors which lead an individual to cross a hypothetical insomnia threshold, eliciting the initial symptoms of insomnia. Perpetuating factors are proposed to play a role in maintenance of insomnia. The neurocognitive model of insomnia [14] is founded on this diathesis-stress model, further integrating neurobiological and neurophysiologic observations and proposes that insomnia leads to conditioned cortical arousal. Hyperarousal on several levels (cognitive-emotional, autonomous and central nervous system) as such is assumed to play a central role in the development and maintenance of adult insomnia [15,16]. Buysse et al. [17], in their neurobiological model of insomnia hypothesized that the activation of cortico-limbic and brainstem hypothalamic centers may account for a relative increase in psychophysiolgical arousal observed in insomnia. The most face-valid animal model of insomnia presented by Cano et al. [18] using a cage-exchange paradigm also described insomnia as a consequence of the stressful experience a co-activation of sleepinducing and arousing neuronal networks . The relationships between response to a stressor and arousal de-regulation have also been Page 3 of 32

integrated in cognitive-psychological models of insomnia [19,20]. Roehrs et al. [21] reviewed evidence from nighttime and daytime electrophysiology, eventrelated brain potentials, neuroimaging, autonomic, and hypothalamic-pituitary-adrenal axis (HPA) studies that suggest insomnia is a 24-hr disorder of hyperarousal. Numerous studies provide evidence for cognitive and physiological hyperarousal with an activation of the HPA in people with chronic insomnia [overview: 15,16,21]. It has been hypothesized that hyperarousal may be a characteristic of individuals with elevated stress-sleep reactivity i.e the degree of sleep disruption in response to stressful events [22-25]. and that hyperarousal may constitute a premorbid characteristic of people with insomnia [22,26].

Sleep disturbances are common in infants and are a normal part of development that affects 20% to 33% of individuals; about half of these develop persistent sleep problems [27-29]. Infant sleep disorders, if not treated, may be quite persistent during childhood [28-29] and through adult life [30-32]. Sleep in the infant has been hypothesized to be influenced by a combination of the process including genetics and environmental factors [33]. A theoretical model of infant sleep regulation integrating multiple environmental systems was developed in 1993 [34] and revised in 2009 (for an overview see [35]). This integrative model emphasizes the role of postnatal environmental stressors in developing infant insomnia [35]. Postnatal-childhood stressful experiences have been associated with life-long consequences in response to stressful events later in life [36-39] leading to a variety of negative health outcomes into adulthood [38,40,41] including increased reactivity to stress [42] and insomnia [31]. Emerging data from both animals and humans indicate that environmental influences contributing to the development of insomnia may not be restricted to periods of postnatal development but may have origins in prenatal life: prenatal stress may contribute to a predisposition for insomnia in animals and humans [43-52].

-Prenatal-early life stress and stress system-implications for insomnia Prenatal and postnatal periods are the most important and sensitive periods during the development of an individual [53,54]. Evidence from preclinical studies indicates that especially the brain is particularly sensitive to remodeling by environmental factors: adverse early-life experiences, such as stress exposure or suboptimal maternal care, can have long-lasting negative consequences leading to 'early-life programming' of individual health and diseases [55].

Although knowledge on the possible mechanisms underlying relations between early-life

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programming' and risk of disorders is limited there is evidence for impaired glucocorticoid negative-feedback control of the HPA axis, altered glutamatergic neurotransmission and reduced hippocampal neurogenesis in both prenatally and post-natally stressed rats (for an overview see [54]). The HPA axis appears to be particularly sensitive to the effects of early life stress [37,54,5660]. Preclinical and clinical studies show the most often proposed mechanism underling the 'earlylife programming' of diseases is that involving the HPA axis and cortisol [54,61-63]. A general pattern, observed in rats and nonhuman primates, is that early stressed offspring tend to show higher basal activity of the HPA axis, as well as potentiated and prolonged HPA responses to stressors with a consistent tendency towards hyper-responsivity (for an overview [54, 63-65]. Decreased feedback inhibition of corticotropin-releasing hormone (CRH) and prolonged elevation of plasma glucocorticoids in response to stress have also been described Prenatal stress rats have higher levels of CRH in the amygdale and fewer hippocampal both glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) [57,64,66,67]. These findings have been integrated within the framework of life history theory [68] High stress responsivity can be adaptive in its nature, may be considered to be predictive for adaptations that serve to improve survival and prepare the organism for a particular range of postnatal unpredictable environments [69]. Enhanced behavioural and neuroendocrine responses to stress may reflect greater vigilance to environmental threats, which may promote survival even if this has a long-term cost of adaptation [70,71]. Accordingly, some theorists have suggested that hyper-responsive HPA axis may have been adaptive during evolution at the cost of vulnerability for various disorders, and may no later be adaptive- even becoming maladaptive or disadvantageous [70,71,72]. Although many individuals experiencing stressful events do not develop pathologies, chronic stress seems to be a triggering factor in those individuals that are particularly vulnerable. This vulnerability may in turn depend upon a permanent increase in the activation of the HPA axis. This can increase the susceptibility of the offspring to various stress related diseases. In fact, there is evidence to suggest that early life stress has been associated with a wide range of health problems later in life such as increase reactivity to stress, psychiatric and behavioral disorders [38,42,64,66,73-75]. Sleep is also one of many outcomes causally linked with early life in the animal literature, showing some changes in sleep architecture and more fragmented sleep related to early life stress, [43,46,47,76-79].

-Epigenetic programming of the stress system- implications for insomnia In the last decade, there is increasing evidence that epigenetic mechanisms are likely to play

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a major role in the molecular mechanisms underlying the long-lasting effect of early life-stress on adult health. The early-life years represent a period of particular susceptibility to epigenetic alteration, as active changes in DNA methylation and histone marks are occurring as part of developmental programs and in response to environmental cues (for an overview see [80]). Epigenetic mechanisms have been hypothesized to shape the responsiveness of the HPA axis to subsequent early life stressors, thus substantially contributing to the development of stable individual differences in HPA hyper-responsivity to stressful stimuli [81-84]. The most investigated hypothesis on how early life stress can alter the child's development in utero and postnatally is that this is mediated by long-term effects on the function/ activity of genes involved in the regulation of the HPA-axis A number of studies have shown that early life stress induced can lead to epigenetic changes in key regulators of the stress-response impairing negative HPA axis feedback by for example, inducing DNA demethylation of the FKBP5 gene thus reducing GR sensitivity which prolongs the cortisol response [85,86] Recently an epigenetic model of insomnia has been proposed [87]. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide a complete understanding of the underlying pathophysiology whereby stress produces long-lasting perturbations of brain and behavior leading to chronic insomnia: stress-response-related brain plasticity might be epigenetically controlled starting from early life [87].

-Hypothesis of the review In this scenario prenatal/early-life stressors might contribute to an 'early-life programming' of the HPA axis and the stress system which may predispose to the development of insomnia in later life. We hypothesize a consistent tendency towards stress system hyper-responsivity in subjects which may be predisposed to develop insomnia: a vulnerability to hyperarousal reactions to life events in the adult may predispose to the development of insomnia. An epigenetic early life shaping of the HPA axis and of the stress system may be implied in the 'early-life programming' of the vulnerability to develop insomnia To this aim we systematically review the evidence about prenatal and early life distress and predisposition to adult insomnia. We then review the hypothesis of its epigenetic programming.

Methods Search strategy We performed a systematic search of MEDLINE, EMBASE and PsychINFO. The initial search was conducted in November 2013 with a final search in April 2014. The search strategies Page 6 of 32

used Medical Search Headings (MeSH) headings and keywords for ‘‘prenatal stress’’or “antenatal stress” or “childhood stress” and ‘‘insomnia” or ‘‘adult insomnia’’ or ‘‘sleep disorder’’ and ‘‘epigenetic”

Inclusion and exclusion criteria Studies were included if they: 1) involved animal subjects or human participants 2) were longitudinal, observational, case-control or cross-sectional studies 3) analyzed the effect of prenatal or postnatal-childhood stress on development of adult insomnia; 4) were published between January 1, 1960 and April 2014. Studies were excluded if: 1) were not available in full text or; 2) were not available in English

Results Ninety articles were retrieved, of these seventy-seven were excluded after detailed review as they did not meet the inclusion criteria. Twenty-four papers were included and their data retrieved. The flow diagram reporting the inclusion and exclusion process through the different phases of the systematic review is presented in Figure 1. Insert figure 1 – please

Prenatal origin of adult insomnia Emerging data from both humans and animals indicate that environmental influences contributing to the development of insomnia may have origins in prenatal life: prenatal response to stress may contribute towards a predisposition for insomnia. Prenatal stress may contribute in predisposing to insomnia in humans and animals [43-51]. -Clinical and psycho-biological hypothesis in humans Although human research into the link between prenatal stress and child function is limited, there is now increasingly evidence to suggest long-lasting effects of prenatal stress on pregnancy outcome and shorter infant sleep duration, some changes in sleep architecture and more fragmented sleep in the infant. Five studies have been included in the review according with the inclusion/exclusion criteria (table 1) Field et al. [48] studied 106 women classified as experiencing high or low anger during the second trimester of pregnancy. The high-anger women showed high prenatal cortisol and adrenaline and low dopamine and serotonin as their neonates' with high cortisol and low dopamine levels. The high-anger mothers and infants were also similar on their relative right frontal EEG activation and

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their low vagal tone. Their newborns had disorganized sleep patterns, greater indeterminate sleep and more sleep-wake state changes In a later study from the same group, Field et al. [49]assessed 253 pregnant women who were recruited during their second trimester of pregnancy (M=22.3 weeks gestation) and assigned to depressed (N=83) and non-depressed groups based on a structured psychiatric interview. They were then given self-report measures regarding sleep disturbance, depression, anxiety and anger, and their urine was assayed for 24 hours norepinephrine and cortisol. These measures were repeated during their third trimester (M=32.4 weeks). Depressed mothers showed high cortisol levels and their newborns had more sleep disturbances including less time in deep sleep and more time in indeterminate (disorganized) sleep, and they were more active and cried/fussed more. In a longitudinal, prospective study of 14,541 pregnancies, O'Connor et al. [50] reported that higher levels of prenatal maternal anxiety and depression predicted reduced sleep duration and more disturbed sleep due to infant night wakings in the newborns at 18 and 30 months after controlling for postnatal mood and obstetric and psychosocial covariates. A delayed onset of consolidated sleep at 18 and 30 months has also been described. In a study from Baird [51] a total of 874 women from the Southampton Women's Survey, were recruited between 20-34 years of age and followed through their subsequent pregnancies and beyond. Prenatal psychological distress was measured with the General Health Questionnaire and was as a strong predictor of infant night waking at both 6 and 12 months of age, independent of the effects of postnatal depression, bedroom sharing, and other confounding factors. The authors concluded that women with prenatal psychological distress are more likely to have babies with infant night wakings during infancy, independent of whether they suffered from postnatal depression.

Nevarez et al. [52] studied 1676 mother-infant pairs in a pre-birth cohort study. Maternal prenatal depression was associated with shorter sleep durations in the infant at both 1 and 2 years of age. Estimates were 0.36 fewer hours/day of sleep in the first two years of life of the infant for maternal prenatal depression. The authors concluded maternal depression during pregnancy to be associated with shorter infant sleep duration. Although the mechanisms relating maternal prenatal stress, mood disturbance, and infant sleep have yet to be fully understood, authors suggested that prenatal maternal anxiety, anger and depression may be associated with increased prenatal stress leading to elevated glucocorticoid secretion. Subsequent to experienced maternal stress an increased activity in the maternal HPAaxis and in

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consequence increased cortisol levels have been observed: it probably also accesses the fetusplacental unit [64,88-90] resulting in the fetal glucocorticoid hyper-exposure [91]. The hypothesized mechanism is that elevated prenatal exposure to glucocorticoids disrupts or programs the fetus’ HPA axis and its diurnal pattern toward a hyperactivation [48-50,52]. A link between the establishment of a diurnal pattern in cortisol and sleeping through the night in infancy has been reported [92]. It may be that exposure to prenatal maternal anger/anxiety/depression and the implied associated increased exposure to glucocorticoids [91] disrupts the onset of cortisol normal diurnal pattern and of a normal sleep cycle in the child. The view hypothesized in human subjects is supported by experimental studies in animals as the vast majority of human studies is, by necessity, descriptive and therefore cannot demonstrate causality or identify the basic mechanisms that underlie pathophysiological processes during development or in adulthood. In addition most of studies in humans subjects measure sleep in young infants and they do not allow to follow the offspring once they have reached adulthood.

-Clinical and psycho-biological hypothesis in animals In order to study the response to stress during prenatal life different animal models of perinatal stress have been developed since 1957 (for an overview see [93]). The sleep–wake cycle has been described to be modified by prenatal stress and significant phase advances have also been observed in the circadian rhythms of locomotor activity relative to the entrained light/dark cycle [43-47]. Dugovic et al. [43] hypothesized that prenatal restraint stress predisposes rats to long-lasting disturbances that persist throughout adulthood. Authors studied sleep–wake parameters in control and prenatally stressed adult rats (3–4 months old) and examined possible relationships with their corticosterone levels (determined at 2 months of age). Under baseline conditions, prenatally stressed rats showed increased amounts of paradoxical sleep which were positively associated with plasma corticosterone levels. Koehl et al. [44] studied the effects of prenatal stress on the daily pattern of corticosterone secretion in male and female rats once they had reached adulthood. Results demonstrated that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis with increased basal levels of corticosterone particularly at the end of the light phase or resting Rao et al. [45] studied adult male rats that had been exposed to retained stress in utero and showed that prenatally stressed animals as compared to non-stressed controls had reduced amount of slow-wave sleep and reduced latency to the onset of rapid eye movement (REM) sleep with a prolongation of the first REM episode. Page 9 of 32

Prenatal stress in animal model has been hypothesized to alter the reactive adaptation of the off spring. Animal investigations have demonstrated that early experiences influence the development of the 24-hour diurnal pattern to the HPA system [94]. Exposure to prenatal restrain stress

has been shown to result in increased responsiveness of the HPA axis to stress

[76,95].Prolonged restraint stress can induce decreased feedback inhibition of

the CHR by

increasing circulating glucocorticoids; prolonged corticosterone secretion has been shown in prenatal stressed rats [95,96]. In addition, prenatal stress exposure results in reduced expression of both GR [97] and MR receptors [96]. in the hippocampus of adult the offspring [76], revealing a possible mechanism for the deficit of HPA axis feedback processes [46,57,6667,95]. The sleep– wake cycle modification in animal model of prenatally stressed rats have been related to alteration in circulating glucocorticoids [43,46,47]. Although much of the animal literature on prenatal stress has focused on the HPA axis activity some authors suggested that prenatally stressed animals may have also higher sympathetic reactivity into adulthood. In a study from Weinstock et al [98], prenatally stress mice displayed a stronger noradrenaline response upon transfer to a novel environment. Dugovic et al 1999 hypothesized that in addition to glucocorticoids, other factors may be involved in the long-term effects of prenatal stress on sleep. As CRH is involved in the regulation of physiological waking by promoting it under both baseline conditions [99] and under stress conditions: CRH may act in inducing an increase in activity of noradrenergic neurons in the Locus Caeruleus [100,101] Thus, permanent neurochemical changes in the activity of the noradrenergic systems might participate in sleep modifications found in prenatally stressed rats. Prenatal life experiences are thus associated with persistent changes in both the modulation of HPA axis activity and the HPA axis-mediated response to stress with a tendency towards and hyperactivity, it may be involved in the predisposition to develop hyperarousal and overstress reactivity in adult life leading to the develpment of insomnia. Indeed other neurochemical changes that have been described to activate the arousal system may be involved as well.

A large body of evidence demonstrate that stress, via elevated levels of glucocorticoids, affects both hippocampal structure and function [71,72,102]. Functionally, chronic stress is generally associated with reductions in hippocampal excitability, long-term potentiation aand morphological consequences of chronic stress include volume reductions and suppressed rates of adult neurogenesis [71,72,102]. Prenatal stress is also associated with a decrease in various stages of adult hippocampal neurogenesis in a lasting manner that persist into adulthood ( for an overview see [53,93,103]. It has been shown to impair the morphological and functional maturation of hippocampal granule cells in

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adult offspring via the downregulated expression of mineralocorticoid receptors [104].

Rats

exposed to some form of prenatal stress seems no longer plastic and are unable to react to experiences that are known to modulate neurogenesis under control conditions, such as learning and stress [103]. A growing number of preclinical studies have shown that prolonged disruption of sleep in rats results in a decrease in neurogenesis and hippocampal cell survival (For review see [105]). Recently hippocampal subfield atrophy has been shown in chronic insomnia suggesting a reduced neurogenesis in the dentate gyrus and neuronal loss in the cornu ammonis subfields in conditions of sleep fragmentation and related chronic stress condition [106]. We may hypothesize prenatal stress to alter hyppocampal neurogenesis in the off spring which may persist into adulthood and be related to insomnia development

-Prenatal life and epigenetic programming of the stress system: implications for developing insomnia Epigenetic modification of gene function may be one mechanism by which prenatal stress may affect the development of the brain and may account for the long lasting effect into adult hood contributing to persisting changes in stress reactivity [64,80,107,108]. DNA methylation could be modulated by exposure to a variety of maternal experiences and might participate in processes that “adapt” the genome to stress. Prenatal exposure to stress conditions has been hypothesized to affect the differentiation of hippocampal neurons and alters hippocampal glucocorticoid receptors gene expression reducing them [81,83,84]. Human infants of mothers with high levels of depression and anxiety during the third trimester have been showed to have increased DNA methylation of the Nr3c1 gene promoter, which may lead to an impaired negative feedback by reducing GR levels (for an overview [107]). There is here is also increasing knowledge of very important roles of placenta in the fetal brain development. Stress during pregnancy may affect the expression of a number of key genes that may alter the permeability of the placenta to glucocorticoids. It possibly happen through alteration of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11ß–HSD2) function that further increases glucocorticoid levels in the fetus and leads to long-term changes in stress hormone regulation. Studies indicate that maternal stress during the prenatal period can lead to a down-regulation of this enzyme: DNA methylation has been hypothesized as a mechanism by which prenatal stress alters HSD11B2 gene expression (for an overview see [86]) Prenatal stress may thus affects the expression of a number of key genes that may alter the permeability of the placenta to glucocorticoids that further increases glucocorticoid levels in the fetus and leads to long-term changes in neurodevelopment. In addition, prenatal stress may also

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directly impact the function of enzymes involved in epigenetic regulation leading to epigenetic effects of prenatal stress and stress hormone regulation. In addition there is evidence for an additional direct transmission of parental or ancestral stress through the germline (for an overview see [86]).This so-called transgenerational epigenetic inheritance may be responsible for the transgenerational inheritance of brain-related phenotypes and disease [109] It was recently reported that mental stress in mouse pups (i.e., separation from the mother) not only changes the DNA methylation status in the brain of the separated pups, but these changes are also transmitted to the next generation. In the next generation, the changed status is visible in the brain of the offspring and is reflected by alterations in the corticotropin releasing factor receptor 2 (Crfr2) gene expression and in the animal’s behavior [110] Multiple perinatal factors can have a transgenerational, lifelong impact on morbidity [111].

Prenatal complex epigenetic effect may in turn modify the responsivity of the HPA axis to subsequent stressors, toward a hyper-responsivity thus substantially, contributing to the development of stable individual differences in HPA responsivity to stressful stimuli [82-84]. It may produce long-lasting modifications of the developing brain and long-term effects on the behavioral and neuroendocrine response to stressors increasing the vulnerability to stress related disorders including insomnia [87]

Childhood origin of adult insomnia Not only prenatal stress but also stress in the early postnatal period after birth have been associated with persistent alterations in the regulation of stress systems and changes in adult stress sensitivity [37-39]. This in turn may increase the risk for a variety of diseases including insomnia [31]. Several studies document the prominent role of childhood stress such as sexual, physical or emotional abuse, emotional or physical neglect, or parental loss, in the pathogenesis of stress related disorders including depression and insomnia [112-113]. Twelve studies met our inclusion criteria in human subjects and four in animals -Clinical and psycho-biological hypotheses in humans Twelve studies met our inclusion criteria in human and and are summarized shown in table 2 [31,79,114-123] (table 2). In a study from Gregory et al. [31]family conflict at age 7-15 predicted the development of insomnia at age 18 (O,R, 1.42 CI-1.17-1.73). This association was present even after controlling for depression at 18 years.

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Childhood adversity was a predictor of sleep disturbance in adult life independently from other psychiatric disorders in a study from Noll et al.[114], conducted on 147 adolescent females. These findings were confirmed in studies from Bader et al. [115,116]conducted in groups of middle aged primary insomniacs. Bernert et al. [117] showed family life stress to be significantly associated with increased insomnia symptomatology in adult life. Koskenvuo et al. [118] in a population based study of 25,605 subjects found that poor sleep quality in the adult life was related to childhood adversity (OR 3.64, CI -2.94–4.50), poor-child mother conflict (OR 10.4, CI- 6.73–16.07), poor child-father conflict. Greenfield et al. [119] showed physical, emotional and sexual abuse to be risk factors for sleep disturbance and poor sleep quality in the adult studying 835 middle aged subjects. Ramsawh et al. [120] confirmed these data in a population of 327 subjects aged 18yrs. This evidence has also been confirmed in other studies: in a retrospective cohort study of 25,810 adult subjects [79] and in a cross-sectional study of 447 adult subjects [121]. Finally, Bader et al. [122] studied 45 primary insomniacs showing a significant association between history of childhood maltreatment and increased beta EEG activity during NREM sleep.

Insert table 2 near here

Stress that is experienced early in life and during sensitive periods of development—such as child who experience abuse, neglect, parental separation or divorce, long-term financial difficulties or severe conflicts in the family, severe illness or alcohol problems in a family member —might fundamentally alter neuroendocrine systems that regulate both the stress system and sleep/arousal system leading to chronic sleep problems [36,124]. Hypervigilance (i.e. hyperarousal) has been described to be a characteristic of subjects with adverse early life experiences [125]; it can persist for many years and may never fully remit [126]. Changes in the nervous and endocrine system appear to render adults with adverse experience in childhood more vulnerable to stress-related disorders and more reactive when confronted with stressors. According to Barlow [127]. hypervigilance in traumatized individuals may be interpreted to reflect the promptness and preparation to deal with potentially negative events. It may be considered an adaptive process of the organism and can then result in the persistence of stress-related neurophysiologic patterns, e.g. chronically elevated levels of catecholamines [128], elevation of HPA axis, resulting in higher stress reactivity in the course of time [129]. Dysregulation of the HPA axis may provide a link between adverse childhood experiences and adult insomnia [79,115,116,118,119,122,123].(Bader et al. 2007,2013, Koskenvuo et al. 2010, Greenfield et al. 2010, Chapman et al 2011). Koskenvuo et al.

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[118] sustained the hypothesis of the latency model [130]regarding the epidemiological life course approach to the effect of negative early-life experiences on adult health: the dose–response association between childhood adversities and adult sleep remained after adjustments for significant adulthood confounder and modifying factors supporting the idea of the direct effect on adult health regardless of adult conditions. -Clinical and psychobiological hypothesis in animals Support for a relationship between early life stress and alterations in adult sleep regulation come from experimental studies in laboratory rodents. One of the most commonly used animal models for early life stress / postnatal stress is maternal separation. The preclinical literature describes some changes in sleep architecture after long maternal separation in rats that is reported to change total sleep time and increase wakefulness compared to non-handled, handled and brief maternally separated conditions [77,78,131,132].

To evaluate the influence of early life environments on basal and cold stress-induced sleep patterns in rats, Tiba et al. [77] studied 3 groups’ male rats (control, early handling, maternal separation) at basal and post stress conditions. Maternally separated rats exhibited more REM sleep at baseline, compared to both control and early-handled rats. The highest corticosterone plasma concentration was observed immediately after stress. The authors concluded that maternal separation during early infancy resulted in permanent changes into adulthood of the sleep architecture reflected by augmented time spent in REM sleep. The authors confirmed these data in a later study: female rats submitted to long term maternal separation exhibited a significant increase of REM sleep on the night following a 1 hour exposure to cold stress, whereas the sleep of brief maternal separation rats was barely altered by stress. The authors concluded that stress condition during infancy may modify sleep architecture [78] Feng et al. [131] applied daily 6 hours of maternal separation form postnatal day 4 to 14 reported that adult maternally separated rats had reduced sleep or increased total wake during the light phase/ resting phase, which might be at least partly related to increased hypothalamic levels of CRH and hipocretin/orexin changes in the adult offspring a. The maternally separated animals further had increased expression of orexin1 recptors in the frontal cortex and increased expression of orexin2 receptors in the hippocampus. The authors conclude that maternally separated rats in adulthood display neurobiological features and sleep patterns characteristic of hyperarousal.

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Mrdalj et al. [132] studied postnatal day 2–14 male rats which were exposed to either long maternal separation (180 min) or brief maternal separation (10 min). Long maternally separated offspring showed a sleep-wake nonspecific reduction in adult EEG power at the frontal EEG derivation compared to the brief maternally separated group. The quality of slow wave sleep differed as the long maternally separated group showed lower delta power in the frontal-frontal EEG and a slower reduction of the sleep pressure. The authors concluded that early environmental conditions modulate the brain functioning in a long-lasting way.

A large body of evidence has shown that neonatal maternal deprivation leads to long-lasting alterations including elevated activation of the hypothalamic pituitary adrenal axis..At the molecular level, maternal depriveted rats show increased plasma ACTH and corticosterone levels at baseline as well as following stressful chanllenge [133]. Also, they exhibit elevated brain CRH levels [134] and hyperexpression of CRH mRNA in the hypothalamus [135]. Further analysis of this model showed that the adult rats, which were neonatally treated with maternal deprivation, had features of insomnia, including decreased total sleep and increased total wake time during the light period [131]. In addition, hypothalamic CRH and orexin A levels are elevated in maternal deprived rats [131].The CRH system is probably partly responsible for some of the behavioral changes and may also be highly relevant in the context of sensitivity to insomnia [131]. CRH which is an important wake promoter both under baseline conditions and stress conditions [99] and also activates other arousal systems such as the hypocretin/orexin system in the lateral hypothalamus and the noradrenergic system in the brain stem may be involved in the regulation of arousal and hyperarousal in the context of insomnia. A reciprocal excitatory interaction between the HPA and the orexinergic system has recently been revealed to occur and substantial evidence suggests a potential involvement of hypocretin/orexin system in high-arousal conditions, including stress has been described (for an overview see [136]). Over expression of components of the orexinergic system for example in the zebrafish, has been shown to induce an insomnia-like phenotype [137]. Mice that over express orexin display sleep abnormalities which include fragmentation of NREM sleep, reduced REM sleep, and increased motor activity during REM sleep, suggesting an inability to maintain sleep states ( for an overview see [138]). Blocking of the orexin system during the night might reduce hyperarousal, thus improving sleep continuity—an assumption supported by earlier preclinical and clinical work [139]. Thus we my hypothesize that postnatal early life stress experiences are associated with persistent changes in both the modulation of HPA axis activity and the HPA axis-mediated response to stress with a tendency towards and hyperactivity, it may be involved in the predisposition to develop

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hyperarousal and overstress reactivity in adult life leading to the develpment of insomnia. Other neurochemical changes that have been described to activate the arousal system may be involved as well including the hypocretin/orexin system and the noradrenergic system Postnatal stress, similarly to prenatal stress has lasting effects on neurogenesis, markers of neural plasticity, synaptic pruning, brain glia, and development of monoaminergic fiber systems and hippocampus, both in rodents and non-human primates [53,140]. Hippocampal plasticity, structure and function are affected in animal model of maternal neglect. Reduced neurogenesis, altered in cell dendritic morphology, reduced in number of hippocampal neurons and glia and reduced fiber density have been reported (For an overviw [54,103,141]) Similarly to prenatal stress we may hypothesize postanatal stress to alter hippocampal neurogenesis in the off spring which may persist into adulthood and to be related to insomnia development.

Postnatal early life epigenetic programming of the stress system: implications for insomnia development Epigenetic mechanisms in childhood have also been hypothesized to shape the adult HPA response to stress and may be implicated in mediating the persistent effects of early-life experience on gene expression in the brain ( for an overview see 83, 103, 107,142-144]. Animal models of perinatal stress have documented sustained alterations in the expression of genes regulating HPA function, such as the GR. As adults, offspring of animals exposed to prenatal stress display life-long epigenetic alterations of the GR promoter in the hippocampus and in the prefrontal cortex [103,142]. It has been proposed that these DNA methylation adaptations early in life is involved in HPA axis shaping that persist into adult life [143,145] The GR/NR3C1 gene encoding the glucocorticoid receptor and involveded in the stress response by regulating the GR espression exhibits differences in DNA methylation and histone acetylation in the hippocampus of the offspring of high and low licking and grooming mothers. Differences in DNA methylation in response to variations in maternal licking and grooming emerged early in life and remained stable into adulthood illustrating that epigenetic [146,147]. Furthermore early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the arginine vasopressin (AVP) gene. Maternal separation in mice persistently upregulates AVP gene expression associated with reduced DNA methylation of a region in the AVP enhancer. Early life stress can dynamically control DNA methylation in postmitotic neurons to generate stable changes in AVP expression that trigger neuroendocrine and behavioral alterations [142].Similar patterns have been observed among humans in recent years. Methylation in the glucocorticoid receptor NR3C1,has also been examined, and three independent research groups reported that a history of childhood abuse was associated

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with altered methylation of NR3C1 in hippocampal-derived DNA [143,144,148] These epigenetic mechanisms that alter the HPA and its response to stress into adulthood are also hypothesized to increase the vulnerability to stress related disorders including depression and post traumatic stress disorder [143,144,148] Postnatal epigenetic, especially DNA metliation, may in turn regualte the responsivity of the HPA axis to subsequent stressors, toward an hyperesponsivity thus substantially, contributing to the development of stable individual differences in HPA responsivity to stressful stimuli. It may produce long-lasting modifications of the developing brain and long-term effects on the behavioral and neuroendocrine response to stressors increasing the vulnerability to stress related disorders including insomnia

Conclusions Models of adult insomnia suggest a predisposition to develop the disorders in response to stressor. Hyperarousal has been hypothesized to be a characteristic of individuals with elevated stress-sleep reactivity; it may also constitute a premorbid characteristic of people with insomnia. Stress is considered to be an important cause of disrupted sleep and insomnia although effects of stress on sleep-wake regulation have been described to be complex depending on several factors [149]. From a life course perspective on health and disease on the basis of the reviewed evidence we may hypothesize prenatal –early life stress to be related to the development of insomnia in newborn and later in adult life. Both prenatal-early life stresses may result in an alteration of the hypothalamicpituitary-adrenal axis which may produce long-lasting amplifications in stress reactivity. It may include effect on the arousal regulating system, such as orexin and noradrenergic systems, and hippocampal neurogenesis that may persist into adulthood. This effect might play an important role in predisposing to a vulnerability to hyperarousal reactions to negative life events contributing to the development of sleep disturbance and evolution to chronic insomnia. It might predispose to vulnerability to stress related hyperarousal and insomnia into adulthood. We might hypothesize epigenetic mechanisms in shaping the response to stress and HPA dysfunction into adulthood secondary to prenatal-early life stress. This may be in line with recent proposed epigenetic hypothesis of insomnia [87]. (Figure 2)

Insert Figure 2 near here References Page 17 of 32

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Figure 1. Flow diagram reporting the flow of information through the different phases of the systematic review.

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Figure 2 Prenatal stress and childhood adversity might interact with the genome producing epigenetic modification in the regulation of the stress system during prenatal life and in the child. It may result in an activation of the hypothalamic-pituitary-adrenal (HPA) axis which may produce long-lasting modifications in stress reactivity that persists into adulthood. It might play an important role in hippocampal neurogenesis and in the regulation of the wake promoting systems , hyporexineorexin, noradrenergic system. HPA axis shaping during early life might play an important role in predisposing to a vulnerability to hyperarousal reactions to negative life events contributing to the development of insomnia. GR: glucocorticoid receptor

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Table 1. Prenatal stress and sleep disturbance in the newborns Authors

Field et al. [48]

Study Design

Study Population

Measure of stress

Sleep Evaluation

Main findings newborn

Longitudinal prospective

106 motherinfant

depression and anxiety scales

Clincal interview

newborns of high-anger mothers had disorganized sleep patterns

SCID diagnosis of depression

questionnaires about sleep in the infant

newborns of the depressed mothers had more sleep disturbances, less time in deep sleep and more time in indeterminate sleep

Anxiety and depression questionnaires

questionnaires about sleep in the infant

GHQ-12

questionnaires about sleep in the infant

higher levels prenatal maternal anxiety and depression predicted more sleep problems in the newborn at 18 and 30 months prenatal distress was associated with increased risk of waking

USA Field et al. [49]

Longitudinal prospective

253 motherinfant USA

O'Connor et al. [50]

Longitudinal prospective

14,541 mother UK

Baird et al. [51]

Longitudinal prospective

874 motherinfant

At 6 months 23% (PR 1.23, 95%- CI 1.06-1.44), at 12 months 22% (PR 1.22, 95% CI-1.02-1.46).

USA

Nevarez et al. [52]

Longitudinal prospective

1676 motherinfant

Anxiety and depression questionnaires

questionnaires about sleep in the infant

maternal prenatal depression was associated with shorter sleep durations in the infant at both 1 and 2 USA years of age Footnotes: SCID: Structured Clinical Interview for DSM, GHQ-12: General Health Questionnaire

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Table 2. Early life stress and insomnia in adulthood Authors

Gregory et al. [31]

Study Design Longitudinal prospective

Study Population

Measure of stress

Sleep Evaluation

137 subjects age 18 years

FES family conflict

Clincal interview

crosssectional

147 females age adolescent USA

self-report for depression, lifetime ACE, PTSD

self-report questionnaire for sleep pattern

sexually abused showed greater rates of sleep disturbances than comparison independently form depression of PTSD.

39 primary insomniacs aged 21-55 years Germany

self-report questionnaire for ACE, current level of stress, arousability, depression

actigraphy

ACE is an important predictors of sleep onset latency, sleep efficiency, number of body movements, and moving time

51 primary insomniacs aged 21-55 years Germany

CTQ

actigraphy polysomnography

46% reported moderate to severe ACE. They show a greater number of awakenings and arousals compared to low or no reports of ACE.

Bader et al. [115]

crosssectional

Bader et al. [116]

crosssectional

Bernert et al. [117]

crosssectional

115 subjects 17-22 years

NLEQ BDI

populationbased

25,605 subjects 20-54 years Finland

self-report questionnaire for ACE child–father and mother relationships BDI

Koskenvuo et al [118]

family conflict at age 7-15 years predicted insomnia at 18 years O.R 1.42 (1.17-1.73)

New Zealand Noll et al. [114]

Main findings adulthood

ISI

self-report questionnaire for sleep quality

Family life stress was significantly associated with increased insomnia symptomatology, even after controlling for depression. poor sleep quality was related to multiple childhood adversities O.R. 3.64 (2.94–4.50)

poor child–mother relationships OR 10.4 (6.73–16.07)

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poor child–father relationships OR 5.4 (3.89–7.50) Greenfield et al. [119]

crosssectional

835 subjects (MIDUS) mean age 54 years

CTQ

PSQI

Physical, emotional and sexual abuse are risk factor for global sleep pathology OR. 3.65 (1.75–7.60)

USA

poorer sleep quality OR 2.58 (1.34–4.96) greater sleep disturbances OR 3.51 (1.80–6.86), greater use of sleep medication OR 2.49 (1.28–4.86) greater daytime dysfunction OR 2.61 (1.38–4.93). Chapman et al. [79]

retrospective cohort study

17,337 subjects aged >18 years USA

CTS

self-report questionnaire

All ACE categories were associated with an increased sleep disturbances (p < 0.05). Subject with ACE reported: OR 2.1 (1.8–2.4) trouble falling or staying asleep OR. 2.0 (1.7–2.3) feeling tired even after a good night’s sleep

Ramsawh et al [120]

crosssectional

327 subjects mean age 18.9 years

self-report questionnaire

self-report questionnaire

Strong significant relationship between childhood adversity and adult sleep quality

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Chapman et al. [121]

retrospective cohort study

25,810 subjects age >18 years USA

CTS

self-report questionnaire

All ACE categories were associated with an increased insufficient sleep (p < 0.05). Subject with ACE reported: OR 2.5 ( 2.1-3.1) insuffcient sleep

Gress-Smith et al [122]

crosssectional

Bader et al. [123]

crosssectional

447 subjects 18-23 years

NSLIJHS PSS CES-D

ISI

45 primary insomniacs aged 21-55 years Germany

CTQ DSM-IV interview for anxiety, depression and sleep diaorders

PSQI polysomnography

ACE is significantly related with insomnia in undergraduate students. perceived stress may partially explain the relation

Significant association between history of childhood maltreatment and increased beta EEG activity during NREM. It may reflect heightened arousal during sleep

Footnotes: FES: Moos Family Environment Scale, ACE:adverse childhood experiences,PTSD Post Traumatic Stress Disorder, CTQ:Childhood Trauma Questionnaire;NLEQ Negative Life Events Questionnaire; BDI:Beck Depression Inventory; CTS:conflict tactics scale, PSQI:Pittsburgh Sleep Quality Index,MIDUS: National Survey of Midlife Development USA.NSLIJHS: Trauma History Checklist and Interview,PSS:Perceived Stress Scale,CES-D: Center for Epidemiological Studies Depression ScaleISI: Insomnia Severity Index,DSM-IV:Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition); NREM: Non Rapid Eye Movemnt Sleep

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