Brain plasticity and early development: Implications for early intervention in neurodevelopmental disorders

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Review

Brain plasticity and early development: Implications for early intervention in neurodevelopmental disorders Plastique cérébrale et développement précoce : implications pour une intervention précoce dans les troubles du développement E. Inguaggiato a , G. Sgandurra a,b , G. Cioni a,∗,b a

Department of developmental neuroscience, IRCCS Fondazione Stella-Maris, Viale del Tirreno 341 A-B-C, 56128 Calambrone, Pisa, Italy b Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Abstract Epigenetics is changing the interpretation of “genetics” in relation to “environment”, in that the genetic code is not exclusively responsible for the “destiny” of a child’s development; environment also has a role in child development. Gene and environment interact over a lifetime and influence maturation of neural circuits and shape changes in physical and mental development. This property, called brain plasticity, is more prominent in early postnatal periods (“critical periods”), which are specific time windows when neural circuits display a heightened sensitivity in acquiring instructive and adaptive signals from the external environment. These periods are not a simple maturation process but represent a complex developmental system that involves different functions (visual, auditory, somatosensory, cognitive ones) and region-specific time courses within specific functional circuits. Several studies have revealed that early experience and environmental stimuli, including parent–infant relationship, nutrition and neuro-endocrine signals, play a critical role in brain development. In this review, the effects of early experience, from bench to humans, on development and neuronal plasticity are discussed, underlining the influences of environment and reporting evidence on the effects of deprived environment. In the second part, the concept of “enriched environment” (EE) is introduced and evidence is reported on the effects of EE and its implications in the field of early intervention for infants at risk of developing neurodevelopmental disorders, in particular for preterm infants. To conclude, recent findings of our group on the use of a novel biomechatronic and tele-monitored system as a tool for early intervention is reported to indicate, for the first time, the feasibility of an intervention based on Information Communication Technology in the first year of life. Despite growing scientific knowledge and evidence regarding the effects of environment on brain development, the mechanisms of this complex interaction are still largely unknown. Further research is still necessary to explore and better understand the influences of environment and the role of early intervention on producing epigenetic modifications, their long term effects, and their relation to age and critical periods. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Brain plasticity; Epigenetics; Early intervention; Preterm infant; Neurodevelopmental disorders

Résumé L’épigénétique change la manière d’interpréter la « génétique » par rapport à « l’environnement », montrant que le code génétique n’est pas le seul responsable du « destin » du développement d’un enfant. L’environnement joue également un rôle crucial dans son développement. Cette propriété, appelée plasticité cérébrale, est plus forte dans les premières périodes de vie postnatale (« périodes critiques »), qui sont des fenêtres temporelles spécifiques lorsque les circuits neuronaux présentent une sensibilité accrue pour acquérir des signaux instructifs et adaptatifs à partir de l’environnement externe. Ces périodes sont considérées non pas comme un simple processus de maturation, mais comme un système de développement complexe qui implique des fonctions différentes (visuelle, auditive, somato-sensorielle, cognitive). Plusieurs études ont mis en évidence que l’expérience précoce et les stimuli environnementaux, y compris la relation parent–nourrisson, la nutrition et les signaux neuroendocriniens, jouent un rôle crucial dans le développement du cerveau. Dans cette revue, nous discutons les effets des expériences précoces, de la paillasse aux humains, sur le développement et la plasticité neuronale, mettant en évidence les influences de l’environnement et rapportant des ∗

Corresponding author. E-mail address: [email protected] (G. Cioni).

http://dx.doi.org/10.1016/j.neurenf.2017.03.009 0222-9617/© 2017 Elsevier Masson SAS. All rights reserved.

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preuves sur les effets de l’environnement carencé. Dans la deuxième partie, le concept d’« environnement enrichi » (EE) est introduit et des preuves sont rapportées sur les effets de l’EE et ses implications dans le domaine de l’intervention précoce chez les nourrissons à risque de troubles du développement neurologique, en particulier chez les nouveau-nés prématurés. Enfin, des expériences récentes de notre groupe sur l’utilisation d’un nouveau système bioméchatronique et télé-surveillé comme outil d’intervention précoce sont présentées. Ils indiquent pour la première fois la faisabilité d’une intervention basée sur les technologies de l’information et de la communication au cours de la première année de vie. Malgré les connaissances scientifiques croissantes et les preuves concernant les effets de l’environnement sur le développement du cerveau, les mécanismes de cette interaction complexe sont encore largement inconnus. D’autres recherches sont encore nécessaires pour explorer et mieux comprendre : les influences de l’environnement et le rôle de l’intervention précoce sur la production de modifications épigénétiques, leurs effets à long terme et leur relation avec l’âge et les périodes critiques. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Plasticité cérébrale ; Épigénétique ; Intervention précoce ; Prématurés ; Troubles du développement

1. Introduction In 1802 the English poet William Wordsworth wrote that “The Child is father of the Man” (“My heart leaps up”, W. Wordsworth, Poems, 1807), a verse that anticipates what would then become one of the oldest debates in scientist and psychological fields: the dichotomy between Nature and Nurture. Nature supposes that individuals and their development are predisposed by DNA and therefore by hereditary factors, while Nurture deems that individuals are the result of life experiences and environment. Over the last decades, the idea that Nature and Nurture can influence each other has gained relevance in this debate. According to this notion, both genotype and environment are necessary but insufficient singularly, to influence the development of individuals and their behaviour. Gene and environment interact, over lifetime, in dynamic “construction” and “deconstruction” processes, which may provide a solution to the nature versus nurture debate [1]. Their complex interaction was defined by Conrad Waddington in 1942 as epigenetic defined as “the branch of biology which studies the causal interactions between genes and their products which bring phenotype into being”. Moreover epigenetic imprinting can be mediated not only by direct genetic modifications but also by transmission of the information across generations in absence of changes in DNA sequences [2,3]. Epigenetic mechanisms can include DNA methylation, histone modifications, chromatin remodelling that influence gene expression without altering them. These mechanisms provide a link between environmental factors and phenotypical changes over the whole lifetime of an organism. Moreover, epigenetic modifications are responsible for tightly regulated tissue and cell-type specific gene expression patterns. In this context, brain development and plasticity have to be considered as the result of the interaction between genes and environment. In fact, while genes guide the initial steps of brain development (e.g. neural tube formation and subdivision in specific regions) and the initial formation of neural connections and neural circuit, environmental factors (stress, diet, drugs, exercise, experience, pathogens) influence its development (e.g. dendritic and synaptic creation, sprouting) by shaping structure and function. In general, brain plasticity is neither good nor bad, it is simply the potential for changes in connectivity, it obeys “electrical” and molecular

rules, but whether the outcome of this change is adaptive or maladaptive depends on how this potential for change is harnessed [4]. Brain plasticity can be distinguished in 3 forms: • experience-independent, genetically determined and independent from external inputs; • experience-expectant and; • experience-dependent, influenced by experience and learning [5]. In general, experience-dependent brain plasticity is shaped by several cellular and molecular factors that regulate the balance between neural excitation and inhibition, neurotrophic action, and intracellular signalling pathway activation (i.e. activation of glutamate N-methyl-daspartate-NMDA receptors), expression of levels of glutamic acid decarboxylase, gamma-aminobutyric acid synthesis and brain derived neurotrophic factor (BDNF). These mechanisms lead to long term potentiation or decrease and gene transcription. Consolidation of long term neural plasticity is regulated by epigenetic mechanisms, that inscribe environmental dynamic experiences on fixed genotype producing a stable alteration of the phenotype [6]. For these reasons, experience-dependent brain plasticity represents the neurobiological basis of neuro-rehabilitation and neuromodulation. In this review we will briefly discuss the effects of early experiences on development and neuronal plasticity, both in animal models and in humans, emphasizing the influences of environment and focusing on its implication in early intervention. 2. Influences of early experiences on brain plasticity and behaviour Several scientific studies, in humans and in animal models, have revealed that early experience and environmental stimuli, including parent–offspring relationship, nutrition and neuroendocrine signals, can influence the maturation of neural circuits and shape changes in physical and mental development. This property, called brain plasticity, is present lifelong, but it is more prominent in the early life, during the so called “critical periods” of brain plasticity (also called “sensitive periods”). Critical periods refer to specific time windows in early postnatal

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life during which plasticity is enhanced and neural circuits display a heightened sensitivity in acquiring instructive and adaptive signals from the external environment, for either development or recovery. These periods are not a simple maturation process but represent a complex developmental system that involves different functions (visual, auditory, somatosensory, cognitive functions) These developmental processes follow region-specific time courses within specific functional circuits. Thus, depending on the developmental stage of a given brain region, positive (e.g. environmental enrichment) as well as adverse environmental factors (e.g. sensory or socio-emotional deprivation, stress, and abuse) can influence neuronal development and thereby adapt functional brain pathways to a given environment, which as a consequence shape brain functional competences and behavioural strategies later in life [4–7]. Classical models used to investigate experience-dependent brain plasticity are deprivation or enhancement of one sensory experience. The deprivation paradigm, in particular, was explored in visual system development in which studies on monocular deprivation induced both dramatic structural and functional changes in the brain such as a massive shift of visual cortical neurons in favour of the non-deprived eye and a strong reduction in visual acuity with loss of binocular vision. Similarly, nutrition seems to influence brain development; lack of one or more essential nutrients, decrease of caloric intake, protein restriction or depletion of omega-3 could be associated with an increased vulnerability of stress system, emotional functions and cognitive development. Feeding behaviour and metabolism are closely regulated by neuro-endocrine mechanisms that are influenced by stressful events and malnutrition and these effects are related to epigenetic mechanisms. At the same time, early physical and psychological stressors seem able to shape the neuro-endocrine system and behavioural responses to stress by activating the hypothalamic-pituitary-adrenal (HPA) axis, that facilitates the release of corticotropin releasing hormone (CRH) and the subsequent secretion of adrenocorticotropic hormone (ACTH) and glucocorticoides (GC) [8]. Moreover, stress events can influence experience-dependent plasticity in that they can interfere with structural and functional maturation of the hippocampus that, during grow, is extremely vulnerability. According to evidence from these models, several studied [9] have shown the association between early adverse life experiences and long term health with increase susceptibility to develop psychopathologies, cognitive deficits and anxiety disorders later on in life due to epigenetic changes in the transcriptibility of some genes. In rat pup models, maternal behaviour represents a crucial factor in the nurturing environment and it is associated with individual differences in vulnerability to stress-related disorders, emotionality and cognitive performance throughout life with long term outcomes [10]. One of the most common postnatal stress models used under laboratory conditions consists of maternal deprivation (MD) or repeated and extensive maternal separation (MS) or low maternal care. These conditions, as stressors, induce hypofunction in a number of brain areas; neuroimaging studies have showed a

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dramatic decrease in metabolic brain activity (especially in the prefrontal cortex) after acute maternal separation and chronic metabolic hypofunction after chronic exposition to maternal separation stress. Moreover, maternal separation seems to activate HPA axis augmenting the hormonal stress response and directly altering intracellular signals which, in turn, determine epigenetic modifications in DNA. Correspondingly, studies in primate models representing more complex social and behaviour relationships when compared to rodents, demonstrate that various stress conditions such as: • chronic and sustained separation from mother during infanthood; • increased stress levels experienced by the mother; • malnutrition determine the disruption of the HPA axis leading to long-lasting anxiety-like behaviours (e.g. strong reactions to social separation, impulsive and aggressive behaviour) and cognitive impairments (e.g. reduction in exploring novel objects). Compared to animal models, humans live in much more complex environments; nevertheless, these general findings are present also in human studies. As showed in several studies, adverse life experiences (e.g., maternal depression, malnutrition or famine, childhood abuse or maltreatment) especially when occurring in early life, might profoundly influence experience-dependent plasticity of the brain thus contributing to development of resilience or vulnerability. Neuroimaging studies in orphanages have revealed a reduction in metabolic activity in the orbital frontal gyrus, the amygdala, hippocampus, lateral temporal cortex and brain stem while white and gray-matter and amygdala volume decreased overall [11]. Other studies have revealed increased endocrine responses to stresses associated with increased vulnerability to psychopathologies, cognitive impairments and learning and memory deficits persistent also in adulthood [12]. In this framework, it is worthy to mention the “Barker hypothesis” regarding the “Foetal Origins of Adult Disease” [13] that exposes the concept of foetal origins of adult disease, whereby stress events, a low birth weight, prematurity, neonatal insults or nutritional factors, occurring during early development, have a profound impact on an individual’s risk for developing future adult diseases, for example coronary artery disease, hypertension, obesity, and insulin resistance. All these findings emphasize the importance of early health care in preventing or reducing risks of chronic diseases. 3. The concept of enriched environment and its effects on brain plasticity and behaviour: findings in animal models To explore the effects of environment on experiencedependent brain plasticity in animal models, in the last decades, the pattern of environmental stimulation has been manipulated and the concept of “enriched environment” (EE) has been

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introduced as an alternative rearing condition to standard conditions. Rosenzweig et al. (1978) have described EE as “a combination of complex inanimate and social stimulation”, carried out in large cages shared by a group of animals, and that include toys, running wheels, and regularly-changing sensorystimulating features, in order to create a range of opportunities for social, visual, somatosensory, olfactory and cognitive stimulation increasing novelty and complexity of voluntary physical activity [14]. Studies on this topic have demonstrated that animals reared in EE when compared to those reared under standard conditions, show a greater experience-dependent cellular plasticity, inducing an enhancement of brain weight, neurogenesis, dendritic branching, synapse formation (e.g. brain weight, cortical thickness, and dendritic structure) [15]. At the same time, it has been demonstrated that EE experiences lead to a significant and consistent improvement in laboratory tasks (e.g. Morris water maze task) involving cognitive functions, especially learning and memory competencies. One of the most significant effects of EE involves the hippocampus, which seems to be particularly sensitive to EE, showing improved (hippocampal-dependent) performance in areas of spatial memory tasks and enhanced learning and memory. EE seems also to have a neuroprotective effect, reducing progressive cognitive decline, attenuating or reversing sequelae of Central Nervous System (CNS) insults such as seizures, ischaemia, infarct, cortical lesions, and traumatic brain injury in animals [6]. These EE effects seem to be mediated by epigenetic factors (e.g. chromatin remodelling, expression of mediators as IGF-1 and BDNF), thus being related to environmental conditions and experiences. However, this paradigm is not so simple. In fact, as reported by Kolb & Gibb [3] environmental factors produce different effects in relation to time of development, type and intensity of stimuli, brain region involved and structure of brain. Influences of EE on brain plasticity have been explored also in pathological conditions through animal models of genetically rare developmental disabilities, autism and cerebral insult models (traumatic injury, stroke or epilepsy), that can considered a wide variety of neurodevelopmental disorders associated with cognitive, motor or social impairments [5,16]. These studies confirm that early EE seems to promote not only structural changes in synaptic plasticity and formation, but also modifies behaviour, enhancing motor coordination and learning (MeCP2y/−mice), reducing hyperactivity (Fmr1-KO mice), repetitive/stereotypic-like activity in animal model of autism and improving memory abilities (Ts65Dn mice). More specifically, in MeCP2y/mice (model of Rett syndrome) early EE increases BDNF level, promotes synaptic plasticity and regulates synapse formation and stability in the cerebral and cerebellar cortex and, on a behavioural level, strongly enhances motor coordination and motor learning [17]. Fmr1-KO mice (model of Fragile X syndrome), reared under enriched conditions, showed a full rescue of hyperactivity and social and cognitive deficits as well as a recovery of alterations in brain dendritic spine morphology [18]. The enriched environment seems have a positive effects in animal models of autism

reducing the time spent in repetitive behaviours, decreased anxiety and enhanced exploratory activity and number of social behaviours and promoted neurogenesis in the dentate gyrus of the hippocampal formation [19,20]. Begenicic et al., [21] have showed in Ts65Dn mice (Down Syndrome model) that enriched mice, compared to wild type, have a reduction of GABA levels in hippocampus and visual cortex and an increase in BDNF level; these molecular effects are related to a robust increase in maternal care levels and to a normalization of declarative memory abilities and a rescue of visual system maturation. In summary, studies on animals that have been enriched in term of physical exercise, cognitive and social stimulation, demonstrate strong evidence of EE effects on brain plasticity in physiological and pathological conditions. The concept of EE, applied in this framework of early intervention, might represent a potential “behavioural therapy” in humans, notwithstanding the necessary caution when translating brilliant results obtained in animal models to human beings. 4. Early intervention, based on enriched environment models, in infants at risk for neurodevelopmental disorders The most common risk factors for NDDs are represented by “Nature” factors such as prematurity, foetal distress, genetic syndrome, brain injury; these conditions in association with the “Nurture” ones such as environmental factors concur in influencing neurodevelopmental outcome. The most important environmental factor, during the early postnatal period, is represented by the infant-caregiver relationship which is a dynamic process between caregivers and infants mediated by complex cognitive functions (sensorimotor activity, attention, emotional signs and responses, reward). An important aspect in this relationship is parental sensitivity to communicative signals of newborns (i.e. gestures, postures, facial expressions, vocalizations, gazes), their recognition and type and predictability of parental responses to them [22]. These aspects, as reported by several researchers, are the basis for establishing balanced affiliative bonds and type of attachment. As postulated by J. Bowlby, in fact, the quality of infant-caregiver relationship has profound and lasting consequences associated with a wide range of developmental outcomes. In this context, preterm infants can be considered at risk for NDDs for two reasons. The first one is nature-dependent and is related to prematurity, that is associated with persistent difficulties across most functional domains and long term neurodevelopmental disorders (such as ADHD, cognitive impairment, behavioural, language and learning disorders). The second is nurture-dependent and mainly due to the quality of the parent-infant interaction: preterm infants could be hypo or hyper-sensitive to environmental stimuli and more easily stressed than healthy full-term infants, and parents could be more or less sensitive to infant signals. Moreover, the consequences on parents of the birth of an at-risk infant should not be overlooked. In fact, this experience, especially for fragile or low resilience subjects, could represent an important negative factor

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that impacts parental mental wellness, who may experience elevated levels of depression, pressure, anxiety and post-traumatic stress symptoms [23]. These symptoms can interfere with early infant parent interactions, promoting the creation of disorganized or maladaptive dyads, increasing the risk for mental and behavioural disorders for infants and also for parents. These negative outcomes take a heavy toll on families, society and the health system and on the future of the children, due to the strong correlation with mental and behavioural disorders in later adult life. Early Intervention (EI) means intervening as soon as possible to tackle problems that have already emerged as a risk condition for neurodevelopmental disorders. This intervention must be directed at both infants and their environment, because acting on environment and especially on parent-infant relationship can promote the of protective factors. This double action will lead to better development outcomes for infants but can also help parents preserve their own good mental health. Environmental conditions seem to be very important for development, especially in early stages, but while the negative impact of deprivation on child development has been largely explored (e.g. studies in orphanages), less is known about the effects of environmental enrichment on infant early development. EE in the field of infant EI could be considered, as proposed by Morgan et al. [24], as an enriched environment for the purposes of promoting learning in at least one of the motor, cognitive, sensory, or social aspects of the infant’s environment. Expressed in these terms, many EI programs could be considered based on EE models. EI programs can begin when infants are still in Neonatal Intensive Care Unit (NICU) or soon after NICU discharge. In the first group of EI, we can mention, as a newborn intervention, the Kangaroo Mother Care (KMC), proposed by Rey (1983) as an alternative to the conventional contemporary method of care for low birth weight (LBW). In KMC, the caregivers are used as “incubators”; the term derived from similarities to marsupial caregiving. The key features of KMC are early, continuous and prolonged skin-to-skin contact between mother and baby, and exclusive breastfeeding (ideally) or feeding with breast milk. Skin-to-skin contact allows the infant to demand care and this contact may trigger neuropsychobiological pathways that improve maternal behaviour and thus increases response to infant needs. The main aim of KMC is to empower caregivers by gradually acquiring skills and accepting responsibilities in order to become the child’s primary caregiver and thus meet all their physical and emotional needs. Evidence from Cochrane reviews [25] support the use of KMC in stabilized LBW or preterm infants and WHO (World Health Organization) recommends KMC as routine care (strong recommendation based on moderate-quality evidence). Another EI program is the Newborn Individualized Developmental Care and Assessment Program (NIDCAP), that covers a range of strategies designed to reduce NICU stress for high-risk infants. Systematic reviews have shown its variable short-term benefits and positive influence on brain function and motor development

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[26]. Moreover, a RCT study on Mother-Infant Transaction Programs (MITP), which obviously involve mothers, has showed that MITP, compared to standard care, improved cerebral white matter micro-structural development in preterm infants [27]. In addition, the Creating Opportunities for Parent Empowerment programme (COPE), designed to enhance parental coping with preterm infants, seems to show a positive effect on trained parents, assuming that facilitation of parental care can improve mental health outcomes and enhance parent-infant interaction [28]. On the other hand, there are several type of post-hospital discharge EI programs that are mainly focused on parent-infant relationship and infant development with the aim of improving overall functional outcome of preterm infants. Interventions can include physiotherapy, psychology, neurodevelopmental treatment, parent – infant relationship enhancement, infant stimulation, infant developmental care and education. Parallel studies on EE in animal and infant models [29] have demonstrated that EE, in terms of body massage and multisensory stimulation (ATVV) performed 3 times per day for 10 days, between 33 and 34 weeks post-menstrual age for preterm infants and at an equivalent age for rat pups, enhanced brain development and in particular the maturation of visual system. These results support the hypothesis that the level of tactile stimulation provided by licking/grooming is an important regulator of brain development and demonstrate and for the first time, that body massage in human infants can influence brain development and accelerate maturation of electroencephalographic activity, visual evoked potentials and visual acuity. Furthermore, this study suggests that the environment acts by modulating level of endogenous factors such as IGF-1, which regulate brain growth and development of visual cortex. The effects of EE in neurodevelopmental disorders have also been studied on both mouse model of Down Syndrome (DS) and DS infants. As previously reported, EE (in term of sensory-motor stimulation) in mouse model of DS (Ts65Dn line) can favour recovery of cognitive impairment, synaptic plasticity failure, and visual deficits. In parallel, Purpura et al. [30] showed that multisensory massage intervention has positive effects also on visual system development of infants with DS. Summarizing, EI programs in humans can represent a form of EE with promising effects on promoting neurodevelopment. However, the reported studies are research programs and one of the limitations on offering a wide diffusion could be represented by the high costs needed for delivering them. For these reasons, tele-rehabilitation programs that through Information and Communication Technologies (ICT) permit remotely managing and home monitoring of EI for a large number of infants could represent new promising solutions. In this framework, our group has recently developed a new technological system for home EI called CareToy (CT, http://www.caretoy.eu ; Fig. 1). The system is composed of sensorised components (such as toys, mats etc.) able to measure grasp-force and grasping-shape, and body movements during play activities. At the same time the system provides an intensive, individualized, home-based, family-centred early

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Fig. 1. a: CareToy System. The figure shows the setting to promote grasping activities in sitting position; b: picture of CareToy Admin, i.e the clinicians’ interface for planning, monitoring and modifying the CareToy intervention; c: details of a grasping action during a goal directed activity; d: details of a scenario with screen wall in prone position and activity aiming to promote both visual and motor abilities.

intervention programme, remotely monitored by a rehabilitation staff [31,32]. In the context of CareToy study, the system was provided at home to preterm infants at risk for NDDs for 4 weeks and the effects of CT intervention were compared to standard

care conditions [33]. Results from the clinical studies (pilot and RCT) provided evidence that CT intervention can provide effective home-based EI. The results [34,35] in fact showed that CT intervention, compared to standard care, significantly

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improve promote motor and visual development in preterm infants. Moreover, CT intervention seems to have a positive influence on parent-infant interaction. In fact, after a CT experience, parents reported: • an increase in shared playing time; • learning new play activities with the infant and; • more involvement in their child’s care [36] (Fig. 1). 5. Conclusion To summarize, epigenetics is slowly changing the interpretation of “genetics” in relation to “environment” in that the genetic code is not exclusively responsible for the “destiny” of a child’s development but that environment also has a role in child development. The concept of epigenetics, which was initially considered irreversible and limited in time, is now deemed dynamic, reversible and verifiable over the course of a lifetime [37]. Relevant epigenetic studies have revolutionized the understanding of the impact of behaviour and environment on brain function and have shed light on how life adversities are linked to development of mental disorders and, on the other hand, how protective factors positively influence neurodevelopment and well-being. In this context, the outcome of neurodevelopmental disorders should be considered in relation to various factors (i.e. genetic, environment and epigenetic) and to their interaction. However, further studies are needed in order to further explore and better understand environmental influences and the role of intervention on producing epigenetic modifications, their long term effects, and their relation to the age and critical periods. Role of funding source The authors of this paper have been partially supported by the Italian Ministry of Health (Grants RC 2016 and RF “CareToy: a smart System for early home-based intervention in infants at high risk for Cerebral Palsy”). Disclosure of interest The authors declare that they have no competing interest. References [1] Robert JS. Embriology, epigenesis, and evolution. Taking development seriously. Cambridge, UK: Cambridge University Press; 2004. [2] Ward ID, Zucchi FCR, Robbins CJ, Falkenberg EA, Olson DM, Benzies K, et al. Transgenerational programming of maternal behaviour by prenatal stress. Ward et al. BMC Pregnancy Childbirth 2013;13(1):S9. [3] Denenberg VH. Evolution proposes and ontogeny disposes. Brain Lang 2000;73(2):274–96. [4] Berardi N, Sale A, Maffei L. Brain structural and functional development: genetics, experience and epigenetics. Dev Med Child Neur 2015;57(2):4–9, http://dx.doi.org/10.1111/dmcn.12691. [5] Kolb B, Gibb R. Searching for the principles of brain plasticity and behaviour. Cortex 2014;58:251–60, http://dx.doi.org/10.1016/ j.cortex.2013.11.012 [Epub 2013 Dec 12].

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[6] Sale A, Berardi N, Maffei L. Environment and brain plasticity: towards an endogenous pharmacotherapy. Physiol Rev 2014;94:189–234, http://dx.doi.org/10.1152/physrev.00036.2012. [7] Bock J, Rether K, Gröger N, Xie L, Braun K. Perinatal programming of emotional brain circuits: an integrative view from systems to molecules. Front Neurosci 2014;8:11, http://dx.doi.org/10.3389/fnins.2014.00011 [eCollection 2014]. [8] Dudley KJ, Li X, Kobor MS, Kippin TE, Bredy TW. Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Neurosci Biobehav Rev 2011;35(7):1544–51, http://dx.doi.org/10.1016/j.neubiorev.2010.12.016 [Epub 2011 Jan 18]. [9] Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009;10(6):434–45, http://dx.doi.org/10.1038/nrn2639 [Epub 2009 Apr 29]. [10] Heim C, Nemeroff CB. Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 2002;7(2):147–59. [11] Mehta MA, Golembo NI, Nosarti C, Colvert E, Mota A, Williams SC, et al. Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the english and romanian adoptees study pilot. J Child Psychol Psychiatry 2009;50:943–51, http://dx.doi.org/10.1111/j.1469-7610.2009.02084.x [Epub 2009 Apr 17]. [12] Seckl JR, Meaney MJ. Glucocorticoid programming. Ann N Y Acad Sci 2004;1032:63–84. [13] Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235–9. [14] Rosenzweig MR, Bennett EL, Hebert M, Morimoto H. Social grouping cannot account for cerebral effects of enriched environments. Brain Res 1978;153:563–76. [15] Gibb RL, Gonzalez CL, Kolb B. Prenatal enrichment and recovery from perinatal cortical damage: effects of maternal complex housing. Front Behav Neurosci 2014 Jun 24;8:223, http://dx.doi.org/10.3389/fnbeh.2014.00223. [16] Nithianantharajah J, Hannan AJ. Enriched environments, experiencedependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006;7(9):697–709, http://dx.doi.org/10.1038/nrn1970. [17] Lonetti G, Angelucci A, Morando L, Boggio EM, Giustetto M, Pizzorusso T. Early environmental enrichment moderates the behavioural and synaptic phenotype of MeCP2 null mice. Biol Psychiatry 2010;67(7):657–65, http://dx.doi.org/10.1016/j.biopsych.2009.12.022 [Epub 2010 Feb 20]. [18] Oddi D, Subashi E, Middei S, Bellocchio L, Lemaire-Mayo V, Guzmán M, et al. Early social enrichment rescues adult behavioural and brain abnormalities in a mouse model of fragile X syndrome. Neuropsychopharmacology 2015;40(5):1113–22, http://dx.doi.org/10.1038/npp.2014.291. [19] Brenes JC, Lackinger M, Höglinger GU, Schratt G, Schwarting RK, Wöhr M. Differential effects of social and physical environmental enrichment on brain plasticity, cognition, and ultrasonic communication in rats. J Comp Neurol 2016;524(8):1586–607, http://dx.doi.org/10.1002/cne.23842 [Epub 2015 Aug 10]. [20] Schneider T, Turczak J, Przewłocki R. Environmental enrichment reverses behavioural alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology 2006;1(1):36–46, http://dx.doi.org/10.1038/sj.npp.1300767. [21] Begenisic T, Sansevero G, Baroncelli L, Cioni G, Sale A. Early environmental therapy rescues brain development in a mouse model of Down syndrome. Neurobiol Dis 2015;82:409–19, http://dx.doi.org/10.1016/j.nbd.2015.07.014. [22] Grossmann K, Grossmann KE, Kindler H, Zimmermann P. A wider view of attachment and exploration: the influence of mothers and fathers on the development of psychological security from infancy to young adulthood. In: Encyclopedia on early childhood development. 2nd rev. Ed; 2009. [23] Poehlmann J, Gerstein ED, Burnson C, Weymouth L, Bolt DM, Maleck S, et al. Risk and resilience in preterm children at age 6. Dev Psychopathol 2015;27(3):843–58 http://doi.org/10.1017/S095457941400087X. [24] Morgan C, Novak I, Badawi N. Enriched environments and motor outcomes in cerebral palsy: systematic review and meta-analysis. Pediatrics

306

[25]

[26]

[27]

[28]

[29]

[30]

E. Inguaggiato et al. / Neuropsychiatrie de l’enfance et de l’adolescence 65 (2017) 299–306 2013;132:e735–46, http://dx.doi.org/10.1542/peds.2012-3985 [Epub 2013 Aug 19]. Conde-Agudelo A, Díaz-Rossello JL. Kangaroo mother care to reduce morbidity and mortality in low birthweight infants. Cochrane Database Syst Rev 2016;23(8):CD002771, http://dx.doi.org/10.1002/ 14651858.CD002771.pub4. Symington A, Pinelli J. Developmental care for promoting development and preventing morbidity in preterm infants. Cochrane Database Syst Rev 2006;2:CD001814. Ravn IH, Smith L, Lindemann R, Smeby NA, Kyno NM, Bunch EH, et al. Effect of early intervention on social interaction between mothers and preterm infants at 12 months of age: A randomized controlled trial. Infant Behav Dev 2011;34(2):215–25, http://dx.doi.org/10.1016/j.infbeh.2010.11.004. Melnyk BM, Feinstein NF, Alpert-Gillis L, et al. Reducing premature infants’ length of stay and improving parents’ mental health outcomes with the Creating Opportunities for Parent Empowerment (COPE) neonatal intensive care unit program: a randomized, controlled trial. Pediatrics 2006;118:e1414–27. Guzzetta A, Baldini S, Bancale A, Ciucci F, Ghirri P, Putignano E, et al. Massage accelerates brain development and the maturation of visual function. J Neurosci 2009;29:6042–51, http://dx.doi.org/10.1523/JNEUROSCI.5548-08.2009. Purpura G, Tinelli F, Bargagna S, Bozza M, Bastiani L, Cioni G. Effect of early multisensory massage intervention on visual function in infants with Down syndrome. Early Hum Dev 2014;90:809–13, http://dx.doi.org/10.1016/j.earlhumdev.2014.08.016 [Epub 2014 Oct 30].

[31] Cecchi F, Sgandurra G, Mihelj M, Mici L, Zhang J, Munih M, et al. CareToy: An intelligent baby gym for intervention at home in infants at risk for neurodevelopmental disorders. IEEE Robot 2016, http://dx.doi.org/10.1109/MRA. 2015.2506058. [32] Rihar A, Mihelj M, Paˇsiˇc J, Kolar J, Munih M. Infant trunk posture and arm movement assessment using pressure mattress, inertial and magnetic measurement units (IMUs). J Neuroeng Rehabil 2014;11(1):133 [Epub 2016 Jun 10]. [33] Sgandurra G, Bartalena L, Cioni G, Greisen G, Herskind A, Inguaggiato E, et al. Home-based, early intervention with mechatronic toys for preterm infants at risk of neurodevelopmental disorders (CARETOY): a RCT protocol. BMC Pediatr 2014;14:268, http://dx.doi.org/10.1186/1471-2431-14-268. [34] Sgandurra G, Bartalena L, Cecchi F, Cioni G, Giampietri M, Greisen G, et al. A pilot study on early home-based intervention through an intelligent baby gym (CareToy) in preterm infants. Res Dev Disabil 2016;53–54:32–42, http://dx.doi.org/10.1016/ j.ridd.2016.01.013 10.1109/MRA. 2015.2506058. [35] Sgandurra G, Lorentzen J, Inguaggiato E, Bartalena L, Beani E, Cecchi F, et al. A randomized clinical trial in preterm infants on the effects of a home-based early intervention with the CareToy System. PLoS ONE 2017;12(3):e0173521, http://dx.doi.org/10.1371/journal.pone.0173521. [36] Inguaggiato E, Sgandurra G, Beani E, Piccardo G, Giampietri M, Bartalena L, et al. [CareToy project for early intervention in infants born preterm: preliminary findings on parent-infant interaction]. G Neuropsichiatria Eta Evolutiva 2015;35:147–54 [in Italian Language]. [37] Carey N. The epigenetics revolution: how modern biology is rewriting our understanding of genetics, disease and inheritance, London Icon Books.