PERINATAL DETERMINANTS OF OFFSPRING NEURODEVELOPMENT ii PRENATAL AND POSTNATAL DETERMINANTS OF OFFSPRING NEURODEVELOPMENT: UNDERSTANDING EARLY NEURODEVELOPMENT AND ASSESSING THE EFFECTIVNESS OF A PREGNANCY NUTRITION AND EXERCISE INTERVENTION By: NEDA MORTAJI, B.Sc. (Hons). A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy McMaster University © Copyright by Neda Mortaji, May 2023 iii McMaster University DOCTOR OF PHILOSOPHY (2020) Hamilton, Ontario (Neuroscience) TITLE: Perinatal determinants of offspring neurodevelopment AUTHOR: Neda Mortaji B.Sc. (Hons) (McMaster University) SUPERVISOR: Dr. Ryan J. Van Lieshout NUMBER OF PAGES: xviii-242 iv Lay Abstract Early brain development is crucial for shaping the cognition, behaviour, and emotions of individuals. Pregnancy is an important time to improve and prevent problems with offspring brain development, and lifestyle factors such as mother’s diet and exercise levels may have a meaningful impact on the developing offspring. Therefore, the objectives of this thesis were to i) identify modifiable risk factors during pregnancy that may affect offspring cognitive and emotion regulation development, ii) understand how these risk factors may affect offspring cognitive and emotion regulation development, and iii) test the effectiveness of interventions aimed at reducing risk factors and improving offspring cognitive and emotion regulation development. Results from this thesis show that improving mother’s diet quality and/or exercise levels during pregnancy may lead to better cognitive and emotion regulation development in offspring during infancy and the preschool years. This thesis suggests that identifying and intervening on risk factors during pregnancy may benefit early brain development in offspring. v Abstract Objectives: To understand the preventive potential of the Developmental Origins of Health and Disease (DOHaD) hypothesis in improving fetal and offspring cognitive and emotion regulation (ER) development by: i) identifying modifiable risk factors during pregnancy that may affect offspring cognitive and ER development, ii) understanding the mechanisms involved in altering offspring cognitive and ER development, and iii) testing the effectiveness of interventions aimed at reducing risk factors and improving offspring cognitive and ER development Methods: Study 1 used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort to examine the effect of prenatal diet quality on executive function (EF) and/or behavioral development in children raised in suboptimal home environments. Studies 2, 3, and 4 are sub-studies of the original Be Health In Pregnancy (BHIP) trial. These studies used a randomized controlled trial (RCT) to test the effectiveness of a pregnancy nutrition and exercise intervention on improving offspring cognitive and ER development at 12 and 36 months of age. Results: Study 1 suggested that healthier maternal diet quality could potentially benefit child executive function and behaviour in 3–4-year-old children from suboptimal home environments. Studies 2, 3, and 4 found that using an experimental approach, the BHIP maternal nutrition and exercise intervention improved various offspring cognitive and ER outcomes across infancy (12- months) and early childhood (36-months). Conclusion: The studies in this thesis highlight the importance of modifiable risk factors introduced during the prenatal period, and their benefits on fetal and child development, and provide the scientific foundation for larger more diverse RCTs to build upon. If results of future RCTs are similar, the BHIP intervention could represent a significant component of the next vi successfully implemented research-enabled public health strategy aimed at improving offspring neurodevelopment. Key words: Pregnancy nutrition, pregnancy exercise, fetal neurodevelopment, cognitive development, emotion regulation development, Developmental Origins of Health and Disease (DOHaD), early childhood vii Acknowledgments I would like to express my deepest gratitude to my supervisor, Dr. Ryan Van Lieshout. Thank you for your endless guidance, support, and patience throughout the past 5 years. Your willingness to go above and beyond for your students is a testament to your dedication to this research and to the success of your students. I am truly grateful for the opportunity to have worked under your guidance and expertise, and will carry the lessons I have learned from you throughout my career. Thank you for everything you have done for me, and for being an exceptional supervisor. I would also like to extend my gratitude to my committee members Dr. Louis Schmidt and Dr. Khrista Boylan for their contributions, guidance, and support throughout this journey. Your kindness and time invested in my research is invaluable to me. I would also like to sincerely thank Dr. Stephanie Atkinson for the opportunity to be a part of the BHIP research, and for her guidance and support throughout the years. Finally, I cannot thank Dr. John Krzeczkowski enough for the constant support, guidance, and time invested in my research. Thank you for always offering me your knowledge and insightful feedback, I feel very fortunate to have worked alongside you. I would like to express my overflowing gratitude and appreciation to my husband Jhonathan, this work would not have been possible without all your constant support and love. Thank you for cheering me on through every success, and lifting me up through every challenge. You are my rock, my source of motivation, and my partner in every sense of the word. Every achievement, milestone, and success that I have reached during this journey is as much yours as it is mine. Thank you for the sacrifices you have made so that I can reach my goals. I would also like to thank my parents and siblings for encouraging me to reach my goals, and for their endless viii support and love. I know you have been patiently waiting for this achievement, and I am beyond happy to share it with you. Lastly, I would like to thank my colleagues and friends that I have made throughout this journey. I am grateful for the many discussions and laughs we have shared, and for your support and encouragement along the way. ix Table of Contents Lay Abstract ...................................................................................................................................iv Abstract ...........................................................................................................................................v Acknowledgements........................................................................................................................vii List of Figures …………………………………………………………………………………...xii List of Tables................................................................................................................................xiii List of Abbreviations .....................................................................................................................xv Declaration of Academic Achievement ......................................................................................xvii Chapter 1 : Background …………………………………………………………………….…...1 1. Prevalence and origins of cognitive, emotional, and behavioural problems across the lifespan………………………………………………………………………………………1 1.2 The developmental origins of health and disease (DOHaD) hypothesis……………………2 1.3 Cognitive and Behavioural Problems and their Development………………………………3 1.3.1 Prenatal Development………………………………………………………………4 1.3.2 Postnatal Development……………………………………………………………...7 1.4 Problems with emotion regulation and its development…………………………………….8 1.4.1 Prenatal Development…………………………………………………………...….9 1.4.2 Postnatal Development…………………………………………………………….13 2. Key Factors Affecting cognitive, behavioural and emotional development in offspring……………………………………………………………………………………14 2.1 Prenatal Determinants………………………………………………………………….14 Maternal nutrition ……………………………………………………………...…..…….14 Maternal exercise…………………………………………………………………………15 Maternal inflammation……………………………………………………………………16 Maternal gestational weight gain (GWG)………………………………………………...16 Maternal infection………………………………………………………………………...17 Maternal distress …………………………………………………………………………17 2.2 Postnatal Determinants………………………………………………………………...18 The home environment…………………………………………………………………...18 Socioeconomic status (SES)……………………………………………………………...18 Child diet/breastfeeding ………………………………………………………………….19 3. Modifiable lifestyle interventions and offspring cognitive and ER development………………………………………………………………………………..19 3.1 Nutrition during pregnancy ……………………………………………………………19 3.1.2 Studies examining maternal nutrition and offspring cognitive and ER development and their limitations………………………………………………………………………..21 3.2 Exercise during pregnancy…………………………………………………………….22 3.2.1 Studies examining maternal exercise and offspring cognitive and ER development and their limitations………………………………………………………………………..23 3.3 Potential synergistic effect of nutrition + exercise……………………………………..24 3.4 The importance of modifiable prenatal factors………………………………………...25 3.5 Lifestyle interventions during pregnancy and their potential to improve maternal and fetal/child health………………………………………………………………………………….26 References………………………………………………………………………………….27 x Chapter 2: Maternal pregnancy diet, postnatal home environment and executive function and behavior in 3- to 4-y-olds (Study 1)……………………………………………………….38 Study overview…………………………………………………………………………..38 Abstract…………………………………………………………………………………..39 Introduction………………………………………………………………………………41 Methods…………………………………………………………………………………..42 Results……………………………………………………………………………………51 Discussion………………………………………………………………………………..56 References ……………………………………………………………………………….61 Chapter 3: Early Neurodevelopment in the Offspring of Women Enrolled in a Randomized Controlled Trial Assessing the Effectiveness of a Nutrition + Exercise Intervention for Optimizing Gestational Weight Gain During Pregnancy (Study 2)…………………………76 Study overview…………………………………………………………………………..76 Abstract ………………………………………………………………………………….78 Introduction………………………………………………………………………………80 Methods…………………………………………………………………………………..81 Results……………………………………………………………………………………85 Discussion………………………………………………………………………………..89 References ……………………………………………………………………………….94 Chapter 4: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 3)……………………………………………………………………...…100 Study overview ………………………………………………………………………...100 Abstract ……………………………………………………………………………...…102 Introduction……………………………………………………………………………..103 Methods…………………………………………………………………………………104 Results…………………………………………………………………………………..107 Discussion………………………………………………………………………………111 References ……………………………………………………………………………...116 Chapter 5: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 4)………………………………………………………………………...122 Study overview ………………………………………………………………………...122 Abstract ………………………………………………………………………………...124 Introduction……………………………………………………………………………..125 Methods…………………………………………………………………………………127 Results…………………………………………………………………………………..132 Discussion………………………………………………………………………………137 References ……………………………………………………………………………...141 Chapter 6: Conclusion ………………………………………………………………………..151 Summary ……………………………………………………………………………….151 The Importance of Modifiable Prenatal Risk Factors and the DOHaD Hypothesis………………………………………………………………………………………152 Mechanisms: How Combined Nutrition and Exercise During Pregnancy Impacts Offspring Cognition and ER From Infancy to Early Childhood ……………………….153 xi Mechanisms: How Combined Nutrition and Exercise During Pregnancy Impacts Offspring HRV From Infancy to Early Childhood …………………………………….156 Synergistic Effects of Nutrition and Exercise During Pregnancy on Postnatal Exposures That May Impact Offspring Cognition and ER………………………………………...157 Limitations……………………………………………………………………………...159 Future Directions……………………………………………………………………….160 Recommendations for Future RCTs Assessing Nutrition and Exercise Interventions and Offspring Cognition and ER Development ………………………………………….…160 Next Steps in Clinical Research: Recommendations …………………………………162 Conclusions …………………………………………………………………………...163 References ……………………………………………………………………………...165 Appendix ………………………………………………………………………………………177 xii List of Figures Chapter 1: Background None. Chapter 2: Maternal pregnancy diet, postnatal home environment and executive function and behavior in 3- to 4-y-olds (Study 1) Supplementary Figure 1: MIREC CD-Plus participant flow chart data at two years of age Supplementary Figure 2: Line graphs for the association between maternal diet quality during pregnancy and working memory, planning scores of the BRIEF-P, and adaptability scores of the BASC-2 in better or poorer home environments Chapter 3: Early Neurodevelopment in the Offspring of Women Enrolled in a Randomized Controlled Trial Assessing the Effectiveness of a Nutrition + Exercise Intervention for Optimizing Gestational Weight Gain During Pregnancy (Study 2) Figure 1: Flow diagram of participants through the BHIP trial Chapter 4: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 3) None. Chapter 5: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 4) Figure 1: Flow diagram of participants through the BHIP trial Chapter 6: Conclusion None. xiii List of Tables Chapter 1: Background None. Chapter 2: Maternal pregnancy diet, postnatal home environment and executive function and behavior in 3- to 4-y-olds (Study 1) Table 1: Demographic information of the MIREC-CD Plus Sample Table 2: Unadjusted associations between maternal pregnancy diet, HOME scores, EF (BRIEF- P), and behavior (BASC-2) outcomes in children at 3–4 y of age Table 3: Adjusted associations between maternal pregnancy diet quality, HOME scores, EF (BRIEF-P), and behavior (BASC-2) outcomes in children at 3–4 y of age Supplementary table 1: Statistical variance of all variables included in the fully adjusted model for each study outcome Chapter 3: Early Neurodevelopment in the Offspring of Women Enrolled in a Randomized Controlled Trial Assessing the Effectiveness of a Nutrition + Exercise Intervention for Optimizing Gestational Weight Gain During Pregnancy (Study 2) Table 1: Maternal characteristics at enrollment and infant characteristics at birth and six months Table 2: Influence of the intervention on infant scaled and composite Bayley-III scores at 12 months of age Supplementary table 1: Measures of the influence of pre-pregnancy BMI, GWG and maternal complications during pregnancy on BSID-III measures for the intervention group by ANCOVA Chapter 4: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 3) Table 1: Maternal characteristics at enrollment and infant characteristics at birth and six months Table 2: 12 Month Infant Heart Rate Variability Metrics scores Table 3: Infant IBQ-R Short Form Scores Supplementary table 1: Correlations between HRV metrics and IBQ-R short form factors Chapter 5: Preliminary Findings of Emotion Regulation in 12-Month Old Infants of Mothers Enrolled in a Randomized Controlled Trial Assessing a Nutrition + Exercise Intervention (Study 4) xiv Table 1: Maternal characteristics at enrollment and infant characteristics at birth and six months Table 2: Maternally Reported CBQ, and BRIEF-P Outcomes of Children at 36 Months of Age Table 3: Impulsivity task scores of children at 36 months of age Table 4: Biological-physiological outcomes of children during baseline and the impulsivity task Chapter 6: Conclusion None. xv List of Abbreviations ADHD: Attention-deficit / hyperactivity disorder ANOVA: Analysis of variance ANS: Autonomic nervous system BASC-2: Behavior Assessment System for Children– 2nd Edition BSID-III: Bayley Scale of Infant and Toddler Development- 3rd Edition BDNF: Brain-derived neurotrophic factor BHIP: Be healthy in pregnancy BMI: Body mass index BRIEF-P: Behavior Rating Inventory of Executive Functioning– Preschool Edition CBQ: Child Behavior Questionnaire CES-D-10, 10-item version of the Center for Epidemiological Studies–Depression COVID-19: Coronavirus disease 2019 DHA: Docosahexaenoic acid DOHaD: Developmental Origins of Health and Disease ECG: Electrocardiography EEG: Electroencephalography EF: Executive function EMI: Emergent metacognition index EPA: Eicosapentaenoic acid EPDS: Edinburgh Postnatal Depression Scale ER: Emotion regulation FAA: Frontal alpha asymmetry FFQ: Food frequency questionnaire FI: Flexibility index FKBP5: FK506 binding protein 5 fNIRS: Functional near infrared spectroscopy GAC: General adaptive composite GDM: Gestational diabetes mellitus xvi GWG: Gestational weight gain HEI: Healthy Eating Index HOME: Home Observation for Measurement of the Environment HPA: Hypothalamic-pituitary-adrenal HF-HRV: High frequency heart rate variability HRV: Heart rate variability IBQ-R SF: Infant Behavior Questionnaire- Revised short form IGF: Insulin-like growth factor ISCI: Inhibitory self control index IQ: Intelligence quotient MIREC-CD Plus, Maternal-Infant Research on Environmental Chemicals–Child Development ƞ²p: Partial eta squared PFC: Pre-frontal cortex PNS: Parasympathetic nervous system RCT: Randomized controlled trial RMSSD: Root mean square of successive differences SD: Standard deviation SDNN: Standard deviation of N-N intervals SES: Socioeconomic status SNS: sympathetic nervous system SPSS: Statistical package for the social sciences UC: Usual care UPC: Usual prenatal care VEGF: Vascular endothelial growth factor VIF: Variance inflation factor xvii Declaration of Academic Achievement This sandwich thesis comprises of 4 studies, each written by the student. She led all formal data acquisition procedures and helped with data collection (studies 2-4). The student cleaned all physiological data pertaining to the studies, conducted all statistical analyses, prepared the initial draft of each manuscript, and revised each paper based on edits from the co- authors. This work was completed between September 2018 and May 2023, therefore, the studies in this thesis meet requirements for inclusion in the text. In accordance with the McMaster School of Graduate Studies requirements, contributions made by each co-author for each study are outlined below. Study 1 examined the effect of prenatal diet quality on Executive function and/or behavioral development in children raised in suboptimal home environments. Neda Mortaji interpreted the study findings, wrote the first draft of the manuscript and incorporated subsequent edits and revisions, and approved the final manuscript as submitted; Dr. John Krzeczkowski conceptualized the idea for this study and its design, analyzed the data, and provided feedback and interpretation of the data; Dr. Khrista Boylan supported data extraction procedures, provided feedback and interpretation of the data, and reviewed and critically evaluated the intellectual content of the manuscript; Dr. Linda Booij contributed to design of the MIREC and cohort study, provided support in the interpretation of findings, and reviewed and revised the manuscript, Dr. Maude Perreault critically evaluated the content of the manuscript and provided feedback and interpretation of the data; and Dr. Ryan Van Lieshout aided in the conceptualization of the idea for the project, helped design the study, provided data analysis and interpretation, critically reviewed and revised the manuscript, and approved the final manuscript form submission. xviii Study 2 and 3 examined whether fetal exposure to a maternal nutrition and exercise intervention lead to better cognition (and physical, communication, social/emotional, and adaptive functioning) and emotion regulation at 12 months of age. Neda Mortaji acquired the data, analyzed all data, interpreted findings, wrote the first draft of the manuscript and incorporated subsequent edits and revisions. Dr. John Krzeczkowski and Dr. Bahar Amani helped with data collection and provided feedback and interpretation of the data; Dr. Stephanie Atkinson contributed to data interpretation and to the intellectual content of the article and provided feedback on subsequent versions of the article; Dr. Louis A. Schmidt supported data interpretation, provided intellectual support for the content of the article and critically evaluated subsequent drafts of the article; and Dr. Ryan Van Lieshout helped conceptualize the idea for the study and interpret the data, provided feedback on intellectual content and on subsequent drafts of the manuscript. Study 4 examined whether fetal exposure to a maternal nutrition and exercise intervention lead to better emotion regulation in children at 36 months of age. Neda Mortaji helped with data collection, acquired the data, analyzed all data, interpreted findings, wrote the first draft of the manuscript and incorporated subsequent edits and revisions. Dr. John Krzeczkowski helped with data collection and provided feedback and interpretation of the data; Dr. Stephanie Atkinson contributed to data interpretation and to the intellectual content of the article and provided feedback on subsequent versions of the article; Dr. Louis A. Schmidt supported data interpretation, provided intellectual support for the content of the article and critically evaluated subsequent drafts of the article; and Dr. Ryan Van Lieshout helped conceptualize the idea for the study and interpret the data, provided feedback on intellectual content and on subsequent drafts of the manuscript. Ph.D. – N. Mortaji; McMaster University–Neuroscience 1 Chapter 1: Background 1. Prevalence and origins of cognitive, emotional, and behavioural problems across the lifespan Early brain development is crucial for shaping the cognition, behaviour, and emotions of individuals, and significantly influences one’s lifelong health and success (Fitzgerald., 2022). In Canada, up to 20% of children are affected by problems of cognition, behaviour, and emotion (Frances et al., 2020). Since up to 70% of these problems have their onset in infancy or early childhood, prevention, along with early detection and intervention is critical to optimizing neurodevelopmental outcomes (Kessler., 2007). Normal brain development is dependent on prenatal and early postnatal conditions (Dyck & Morrow., 2017). Research suggests that the first “1000 days” of life (beginning at conception) are a critically important period that sets the foundation for healthy brain development across the lifespan (Likhar et al., 2022). This period is also characterized by substantial developmental change and heightened neuroplasticity (Cusick et al., 2016). During this time, the brain is highly responsive to environmental cues that influence neural network development. Such exposures include maternal nutrition, stress, infection and the home environment, among others (Fitzgerald., 2022). Advances in neuroimaging have established that numerous mental and neurological disorders are due to altered prenatal brain development (Vasung et al., 2019). The perinatal period, and more specifically the prenatal period is therefore a key time to intervene and potentially prevent and/or reduce the impact of adverse experiences on the development of cognitive, behavioural, and emotional problems (which are more difficult and expensive to address later) (Howard et al., 2020)). Ph.D. – N. Mortaji; McMaster University–Neuroscience 2 1.2 The developmental origins of health and disease (DOHaD) hypothesis Formal recognition of DOHaD became much more widespread in the 1990s as epidemiological studies reported associations between geographic locations with high infant mortality and high adult mortality from heart disease (Mandy et al., 2018). This observation was made by Dr. David Barker, which is why the DOHaD hypothesis was often referred to as the Barker hypothesis earlier in its emergence (Wadhwa et al., 2009). From this observation, Dr. Barker defined the DOHaD hypothesis as environmental exposures during sensitive periods of fetal development can influence health and susceptibility to disease later in life (Hoffman et al., 2017). The hypothesis posits that environmental conditions such as maternal nutrition, obesity, stress, or infection can have programming effects on multiple fetal organ systems (Fitzgerald et al., 2020). However, it was later better appreciated that both adverse prenatal and early postnatal conditions can influence susceptibility to disease later in life. Initially, the DOHaD field focused primarily on outcomes related to cardiovascular and metabolic health, diabetes and obesity (Heindel et al., 2015). However, the DOHaD hypothesis has now broadened to more frequently examine neurodevelopmental outcomes such as cognitive, behavioural and emotional outcomes. The past few decades of evidence have now supported a link between perinatal exposures and child neurodevelopmental outcomes. It has been hypothesized that developmental plasticity underlies the longer-term impacts of fetal and early postnatal life exposures on brain development and its associated disorders. Developmental plasticity is the ability for a phenotype to change depending on environmental cues during sensitive periods such as the prenatal and early postnatal periods (Lea et al., 2017). The phenotypic outcomes that develop during these periods are considered to remain throughout one’s life (Monoghan et al, 2008). Therefore, Ph.D. – N. Mortaji; McMaster University–Neuroscience 3 adverse environmental conditions during these periods may lead to altered phenotypes and lifelong neurodevelopmental problems. Therefore, perinatal exposures during sensitive periods of development can affect cognitive and ER development, and lead to lifelong susceptibility to problems and disease. However, although brain plasticity decreases with age and prenatal interventions may provide the best means of reducing neurodevelopmental problems, the majority of research in the DOHaD field is observational in nature. In order to unlock the clinical potential of the DOHaD hypothesis and test its scientific validity, more rigorous experimental studies in humans (i.e., RCTs) are needed. 1.3 Cognitive and Behavioural Problems and their Development Cognition has been defined as the ability to acquire, process and store the information required to understand and effectively interact with one’s environment. Cognition is a complex and multifaceted concept that is central to other processes such as behaviour and emotion regulation (Arioli et al., 2018). Cognition includes functions like attention and memory, as well as higher order mental processes referred to as executive functions (Khera & Rangasamy., 2021). Executive function is required for the cognitive control of behaviour and consists of factors such as working memory, planning, flexibility, and inhibition (Friedman et al., 2022). These skills are central to daily functioning, academic success, social relationships, and self regulation (Reilly & Downer, 2020). Behaviour is defined as observable actions one takes or a reaction in response to their environment (Jhangiani et al., 2022). Both cognitive and behavioural development are core to shaping interpersonal relationships, academic success, and subsequent mental health, and predict overall health as well including premature mortality (Pietromonco & Collins., 2018). Since the overall architecture of the brain has developed by 6 months of gestation, it is important Ph.D. – N. Mortaji; McMaster University–Neuroscience 4 to understand the development of cognition and behaviour prenatally so that we can determine how to prevent problems and optimize functioning (Baburamani et al., 2019). 1.3.1 Prenatal Development The early stages of cognitive and behavioural development in the first trimester involve neural tube formation (Singh et al., 2022). The neural tube eventually forms into the brain and spinal cord which sets the foundation for processes such as neurogenesis to occur (Prado et al., 2014). Neurogenesis involves the process of cell division in the brain to lead the growth and interplay of various brain regions such as the limbic system (which includes the hippocampus, hypothalamus and amygdala), the prefrontal cortex (PFC) and cerebral cortex (Bremner et al., 2006). These brain regions begin to develop via the processes of neural proliferation, differentiation, migration and circuit formation (Hwang et al., 2019). During the second trimester of pregnancy, a set number of neurons and glial cells then migrate to the different regions of the brain in response to chemical signals that ensure cell movement to correct locations in the brain (Molnar et al., 2015). The number of cells that migrate to each brain region influences the function, size and connectivity of the region (Belmonte-Mateos et al., 2019), and so the fewer neural cells that migrate to brain regions associated with cognition and behaviour, the more cognitive and behavioural deficits can develop (Hwang et al., 2019). Once neural cell migration is complete, brain regions begin forming neural circuits by creating synaptic connections between neural cells in order to communicate with different brain regions (Tau et al. 2010). The strength of these neural circuits is influenced by the number of neural cells at each brain region as well as the number of neural connections they form (Daught et al., 2017). Ph.D. – N. Mortaji; McMaster University–Neuroscience 5 Multiple neural circuits are important to the development of normative cognitive and behavioural functioning, and they are primarily established in utero (Tau et al., 2010). First, in the second trimester, the sensory circuits between the visual and auditory cortex form in the superior temporal sulcus (Hickok et al., 2009). These circuits begin to develop and activate in the fetus in response to external stimuli such as sound and light (Fagard et al., 2018). When these circuits are activated, they are strengthened and begin to form neural circuits with other brain regions (hippocampus, amygdala, PFC, temporal lobe) important for additional cognitive functions such as memory, attention, and perception (McEwen et al., 2016). Therefore, these sensory experiences shape fetal cognitive development by strengthening sensory circuits and creating additional circuits that are needed for more complex cognitive development (Tierney et al., 2009). Language circuits involved in the comprehension (Wernicke’s area) and production (Broca’s area) of language also begin to develop in the second trimester (Kunert et al., 2015). The arcuate fasciculus (bundle of nerves that goes through the frontal and temporal lobes) connects Broca’s and Wernicke’s areas (Catani et al., 2008). The arcuate fasciculus in the fetus is activated in response to language exposure (from the second trimester) which strengthens and matures the circuits between Broca’s and Wernicke’s areas (Romeo et al., 2018). This may be the reason that studies have found that fetuses who were exposed to more language in utero develop more advanced language abilities in infancy and childhood (Moon et al., 2013). Similarly, the maturation of language circuits leads to the development of additional neural circuits responsible for motor coordination and memory (Goto et al., 2022). Lastly, the hippocampal-PFC-amygdala circuit is important for a variety of cognitive and higher-order cognitive development (i.e., problem solving, memory formation, learning, Ph.D. – N. Mortaji; McMaster University–Neuroscience 6 emotional processing) (Tyng et al., 2017). This circuit begins to develop in the second to third trimester and is strengthened by sensory inputs as well as maternal nutrition (Smic et al., 2021). Like other circuits, it is activated and strengthened by external inputs such as voices, sounds, and tastes (the last of which is particularly sensitive to nutritional inputs (Tau et al., 2010)). Good maternal nutrition leads to better growth and development of these brain regions and the synaptic connections between them, and in turn strengthens the hippocampal-PFC- amygdala circuit (Zimmerman et al., 2019). Likewise, poor maternal nutrition can disrupt the development of this circuit and lead to numerous cognitive deficits (Cortés-Albornoz et al., 2021). Therefore, the development and strengthening of neural circuits involved in cognitive development can lead to the formation of additional circuits between many brain regions important to cognition (Khalil et al., 2019). In turn, the fetus develops a larger and more complex functional connectome (network of neural connections between brain regions) (Turk et al., 2019). Research has suggested that the fetal connectome can provide significant insight on the cognitive development of offspring postnatally, such that larger connectomes may lead to better cognitive development in offspring (Cao et al., 2017). In the third trimester, the rapid development of the cerebral cortex begins which is the outermost layer of the brain, and is important for higher-order cognitive and behavioural processes such as decision making and problem solving (Vasung et al. 2019). Since the cerebral cortex consists of the frontal, parietal, occipital, and temporal lobes, its development (specifically the frontal lobe) prenatally is key to cognitive and behavioural development (Tierny et al., 2009). The frontal lobe is important to cognitive and behavioural development and is related to functions such as adaptive behaviour, social interactions, problems solving and executive functions (Rabinovici et al., 2015). Adverse prenatal exposures such as poor nutrition, stress and Ph.D. – N. Mortaji; McMaster University–Neuroscience 7 substance abuse can disrupt the synaptic connections within the frontal lobe and its connections with the parietal (attention and special processing), occipital (motivation and memory), and temporal lobes (language and facial processing) (Arain et al. 2013). These synaptic connections are key to integrating information between different brain regions, which is required for higher order cognitive processes (Bassi et al., 2019). Therefore, positive prenatal exposures such as healthy maternal nutrition can strengthen synaptic connections within the frontal lobe and across the other lobes in the cerebral cortex (as well as form additional connections within the cerebral cortex) (Franke et al., 2020). Research has also suggested that increased synaptic connections between the lobes can lead to better cognitive and behavioural performance later in life (Kolb et al., 2011). Therefore, it may be implied that cognitive and behavioural development begin prenatally, and set the foundation for brain development postnatally. 1.3.2 Postnatal Development Cognitive and behavioural development is a continuous process that continues to develop from birth through adulthood, but during the first three years of life, the most rapid brain growth and development occur (Tierney et al., 2009). At this time, cognitive and behavioural development is influenced by experiences and external stimuli that form new neural connections and strengthen prior connections between brain regions (Kolb et al., 2011). Experiences such as stimulating home environments, parental support and caregiving, as well as stress, abuse and social relationships affect brain development, and can have long-term implications (Ilyka et al. 2021). Positive experiences increase neural connectivity and activation in brain regions associated with cognitive and behavioural development, and strengthen neural connections so that they become more effective and efficient (Tierney et al., 2009). Additionally, the early postnatal period is characterized by a period of synaptic pruning, where weaker neural Ph.D. – N. Mortaji; McMaster University–Neuroscience 8 connections are discarded, and the remaining neural connections are strengthened to facilitate the development of higher order mental processes (Cardozo et al., 2019). Therefore, providing positive and enriching prenatal and postnatal environments can ensure the proper development of cognitive and behavioural outcomes across the lifespan. 1.4 Problems with emotion regulation and its development Emotion regulation (ER) is defined as the ability to modify one’s emotions in response to ongoing demands (McRae et al, 2020) and its application has been hypothesized to occur in two ways. The first way is referred to as top-down ER, which refers to the conscious use of cognitive functions (i.e., distraction, mindfulness) and thinking to regulate emotions and physiological responses in response to a stimulus (Guendelman et al., 2017). Top-down activation of ER is often associated with the activation of brain regions such as the PFC and the anterior cingulate cortex (Chisea et al., 2013). These brain regions underlie cognitive functions such as attention and problem solving which may be involved in regulating an emotional response (Friedman et al., 2022). The second way refers to bottom-up ER, which refers to the unconscious and often immediate physiological response towards a stimulus (i.e., instant fear) (McRae et al., 2012). Bottom-up activation of ER often involves the amygdala (key brain region for emotional processing) and the hypothalamus (aids in regulating the stress response to a stimulus) (Simic et al., 2021). These regions help regulate heart rate and breathing, which are important aspects of bottom-up ER (Ikeda et al., 2017). Both top-down and bottom-up ER are often used in combination with one another, however, researchers suggest that bottom-up ER often occurs first (unconscious response to a stimulus), followed by top-down ER once the individual has had time to process the physiological response. Ph.D. – N. Mortaji; McMaster University–Neuroscience 9 Historically, it was assumed that ER developed only after birth, but more contemporary evidence suggests that ER development begins in utero (Allen et al., 2015). One study found that the fetus can portray facial expressions such as disgust or sadness in response to stimuli in the second and third trimesters using 4D ultrasound technology (Abo Ellail et al., 2018). Other work suggested that the fetus can exhibit different heart rate patterns and movement in response to different stimuli (Marx et al., 2015). These studies led to the discovery and understanding that fetuses have ER abilities, and that prenatal exposures can affect fetal and later offspring ER development (Ross et al., 2015). This is not surprising since prenatal exposures have been found to affect the development of brain regions such as the amygdala and the PFC which are involved in ER development in the fetus and later in life (Pulli et al., 2019). The prenatal and postnatal development of ER will be discussed in sections 1.4.1 and 1.4.2. Problems with ER very early in life have been linked to an increased risk of substance misuse, criminal conviction, mental health problems, risk-taking behaviour and physical health problems including cardiovascular disease (Bradizza et al., 2018). 1.4.1 Prenatal Development Similar to cognitive and behavioural development, ER begins to emerge prenatally in the first trimester through the process of neurulation which forms the neural tube to develop into the brain later (Chhetri et al., 2021). During the second trimester, processes such as neural cell proliferation, migration and synaptic connections form between key brain regions (Kolk et al., 2022). Such regions include the limbic system, PFC, insula and the anterior cingulate (Teffer et al., 2012). However, the development of ER is also dependent on a series of other processes such as the balance of neurotransmitters, epigenetic modifications of genes, and the development of the somatosensory system involved in regulating emotions (Simic et al., 2021). Ph.D. – N. Mortaji; McMaster University–Neuroscience 10 Neurotransmitters such as serotonin, dopamine, GABA and glutamate are critical in preparing the brain for postnatal life (Bolneo et al., 2022). First, they aid in the development of plasticity in brain regions, allowing them to accommodate to changing experiences and environments (Egerton et al., 2020). Second, these neurotransmitters play a key role in the regulation of fetal breathing, heart rate and movement, factors that are believed to mediate ER (Sarawagi et al., 2021). Third, they support the formation of neural circuits involved in ER such as the amygdala-PFC-insula circuit that connects through the corticolimbic network (Qui et al., 2015). This circuit involves brain regions key to emotional processing and regulation, and disruptions to the neurotransmitter systems (serotonergic, noradrenergic, dopaminergic) from adverse prenatal exposures (i.e., maternal stress, poor nutrition), can alter and weaken this circuit (Godoy et al., 2018). This circuit is important for prenatal ER development as it may help the fetus regulate emotional responses from external and internal stimuli which they are able to process from the second trimester (Ross et al., 2015). Lastly, neurotransmitter system support the expression of genes involved in ER and the stress response through epigenetic processes (Sarawagi et al., 2021). Epigenetics is the study of how external influences can affect gene expression without altering the DNA sequence (Al Aboud et al., 2022). These changes in gene expression may be caused by modifications in DNA that regulate when genes are turned “on” or “off” (Handy et al., 2011). Epigenetic modifications in response to external stimuli may play an important role in how genes are expressed and regulated, and may have a strong impact on fetal and offspring neurodevelopment (Kundakovic et al. 2017). The most studied epigenetic modifications include DNA methylation (adding or removing a methyl group from DNA or proteins) and histone modifications (modulation of chromatin structure that affect DNA processes) (Banik et al., Ph.D. – N. Mortaji; McMaster University–Neuroscience 11 2017). These epigenetic modifications occur in response to prenatal exposures such as maternal nutrition or stress (Li et al., 2019). Adverse prenatal conditions have been suggested to alter DNA methylation and histone modifications and affect gene expression related to neural differentiation, synaptic plasticity, neurotransmitter signalling, and the stress response in brain regions such as the PFC and amygdala (Matosin et al., 2017). The most well studied genes affected by these epigenetic modifications are genes FK506 binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF) which are involved in ER (Mourtzi et al., 2021). The FKBP5 gene is involved in the regulation of the stress hormone cortisol (and the stress response system), and studies have suggested that prenatal exposures such as maternal stress or undernutrition can lead to changes in DNA methylation in this gene which can lead to a decrease in expression of the FKBP5 gene and increased cortisol signalling in the fetus which can alter the fetal stress response system both prenatally and postnatally (Zannas et al., 2016). Studies have suggested increased cortisol signalling prenatally may be associated with greater emotional reactivity later in life (McGowen et al., 2018). On the other hand, histone modifications may alter the BDNF gene (a protein important for the growth and development of neurons in the brain) in brain regions such as the hippocampus (involved in ER) (Kowianski et al., 2018). Adverse prenatal conditions may lead to changes in histone modifications that decrease levels of the BDNF gene in the hippocampal tissue, which can alter emotional responses in the fetus and later in life (Kundakovic et al., 2017). Therefore, epigenetic modifications in response to adverse prenatal exposures may be involved in the development of emotion regulation and dysregulation and lead to long lasting changes in gene expression that may affect ER (Jiang et al., 2019). During the second and third trimesters, the development of the somatosensory system also begins, which permits the fetus to process and respond to various stimuli such as maternal Ph.D. – N. Mortaji; McMaster University–Neuroscience 12 touch which may optimize emotional regions of the brain such as the amygdala (emotional center of the brain) and improve the function of the stress response system (Simic et al., 2021). Non- human animal studies have suggested that maternal touch during pregnancy led to an increased number of neurons and synapses in the amygdala (which optimizes the development of the amygdala and strengthens its connections with other brain regions to further improve ER) (Stoye et al., 2020). Additionally, maternal touch led to an increase in the expression of genes such as BDNF genes involved in synaptic plasticity in the amygdala (Colucci-D’Amato et al., 2020). Synaptic plasticity in the amygdala is important for the adaptation of emotional responses to changing environments, which is a key construct of ER (Bathina et al., 2015). Lastly, maternal touch may lead to a decrease in the (hypothalamic-pituitary-adrenal) HPA axis activity and cortisol levels which can reduce the stress response and prevent hyperactivity in the amygdala (Herman et al., 2016). Therefore, positive prenatal exposures may affect the development and functioning of the amygdala and improve the stress response system, in turn optimizing ER development. However, studies also support that adverse prenatal exposures such as the emotional state of the mother can affect fetal ER and the somatosensory system by exposing the fetus to increased levels of cortisol (stress hormone) which hinders their development (Glover et al., 2015). Increased levels of cortisol can cause hyperactivity of the HPA axis system and the amygdala, leading to dysregulation in emotions (Sheng et al., 2021). A range of other external factors also influence the development of ER prenatally, such as maternal stress, mood disorders, sub-optimal nutrition, physical inactivity, and substance misuse (Lewis et al., 2014). These maternally mediated exposures affect the development of gray matter volume in brain regions such as the PFC, anterior cingulate and insula, key regions that facilitate fetal ER, as well as its markers including heart rate variability (HRV) (Marečková et al., 2019). Ph.D. – N. Mortaji; McMaster University–Neuroscience 13 HRV is a measure of fetal autonomic nervous system regulation and is one of the earliest emerging markers of later stress reactivity (Pham et al., 2021). Reduced fetal gray matter volume in these brain regions has been linked to poorer emotion regulatory capacity in infancy and early childhood (Marečková et al., 2019). Therefore, the prenatal development of ER can set the foundation for emotional processing and control after birth through these exposures and their resultant epigenetic changes (Kundakovic et al., 2017). 1.4.2 Postnatal Development The first three postnatal years provide an important window for the continued development of ER by providing opportunities for the learning and teaching of emotional abilities to infants and children (Nelson et al., 2019). The development of ER during infancy and early childhood generally consists of several different factors. During infancy, ER is developed primarily through the quality of caregiver regulation and attachment style (Fernandes et al., 2021). Caregivers (still most frequently mothers) are the main source of emotion regulation for infants, and this is optimally accomplished by responding appropriately and sensitively to cues of distress in their infant. When caregivers effectively calm their infants, infants can develop a secure attachment style and are better able to independently regulate their emotions both during infancy, and later in life (Taipale et al., 2016). As infants enter early childhood, the primary influences on ER development shift from caregivers to themself (Perry et al., 2018). Neuroanatomically, ER development in early childhood is characterized by the maturation of the PFC, a key brain region in shaping ER (Hodel et al., 2018). During the maturation of the PFC, functions critical to ER such as working memory, inhibition of impulsive behaviour, cognitive flexibility, and regulatory strategies such as distraction begin to emerge and contribute to ER development and optimal social interactions. Ph.D. – N. Mortaji; McMaster University–Neuroscience 14 Another important influence on ER development in early childhood is socialization and modelling. As children socialize with others, they learn to respond in emotionally appropriate ways, especially if they observed positive behaviours from caregivers (Ornaghi et al., 2021). 2. Key Factors Affecting cognitive, behavioural and emotional development in offspring 2.1 Prenatal Determinants Maternal nutrition: prenatal nutrients provide the building blocks needed for optimal brain development to occur (Kadosh et al., 2021). These include fatty acids, amino acids, vitamins, and minerals. Deficiencies and/or imbalances in these can contribute to problems with the development of the systems underlying cognition, behaviour and emotions (Cusick et al., 2016). Although every nutrient plays an important role in the developing fetal brain, a list of the crucial and well-studied nutrients will be described in this section. First, adequate maternal nutrition is required for the development of the brain’s structure and its neural processes that initiate brain development (Cheatham et al., 2019). Very early in fetal brain development, nutrients such as folate are required for neural proliferation and differentiation, guiding neural tube formation - the first step in brain development (Balashova et al., 2018). Neural tube defects occurring as a result of a lack of folate, may lead to abnormalities in brain development present in conditions such as spina bifida (Greene et al., 2014). Processes such as myelination and synaptic formation require nutrients such as iron and omega-3 fatty acids respectively (Tardy et al., 2020). Iron is important for myelin development which is necessary for efficient neuronal transmission of neurons (Mills et al., 2010), and omega-3 fatty acids aid in the formation of synaptic connections between neurons of brain regions (Dyall et al., 2015). However, a combination of nutrients is required for optimal development of the structure of the brain. Adequate nutrient consumption, specifically protein intake, can determine the size and function Ph.D. – N. Mortaji; McMaster University–Neuroscience 15 of brain regions important for cognitive and emotional development such as the PFC and amygdala (Kadosh et al., 2021). Maternal nutrition can also affect fetal cognitive and emotional development by influencing gene expression and epigenetic modifications that alter the expression of genes (Banik et al. 2017). Nutrients such as choline and protein can enhance gene expression and alter DNA methylation patterns of genes involved in the development of cognitive and emotional brain structures and their functions (Thorsell et al., 2016). Third, non-human animal studies have reported that poor maternal nutrition consisting of a diet high in fat and sugars have been suggested to impact neural circuitry important for cognition and ER, and lead to problems like cognitive impairments and mood disorders later in childhood. Moreover, such a diet can lead to additional problems such as inflammation and obesity (discussed later in this section) which can affect fetal cognition and ER (Parlee et al., 2014). Maternal exercise: exercise during pregnancy can provide benefits to the fetus that may improve cognitive and emotion regulation development. The primary benefit of maternal prenatal exercise includes supporting the development of the placenta (Chae et al., 2022). The placenta is responsible for blood, oxygen and nutrient delivery to the fetus, and exercise can enhance the blood flow of oxygen and nutrients to the developing brain regions so they can optimally develop and form synaptic connections (Gaccioli et al., 2016). Another benefit of maternal exercise is that it can result in an increase in levels of neurotrophic factors in the brain such as BDNF and vascular endothelial growth factor (VEGF) (Cho et al., 2022). These neurotrophic factors support the development and survival of neurons and have been linked to improved cognitive and emotion regulation development (Sleiman et al., 2016). Lastly, exercise during pregnancy can prevent or reduce complications such as gestational diabetes mellitus Ph.D. – N. Mortaji; McMaster University–Neuroscience 16 (GDM), preeclampsia, inflammation, or stress in pregnant women, which have been linked to adverse fetal cognitive and emotional development (Wang et al., 2016). However, exercise during pregnancy must be monitored and controlled by health care providers as elevated, excessive levels of exercise (e.g., intense stair running) may lead to adverse effects on the fetus, specifically later in pregnancy (Cooper et al., 2022). Maternal inflammation: prenatal inflammation can adversely affect both maternal and fetal health. Specifically, maternal inflammation interrupts the process of neurogenesis, which involves the formation of new neurons in different regions of the brain (Kohman et al, 2013). Dysregulation of neurogenesis may lead to cognitive and emotional deficits as there are fewer neurons available (Leuner et al. 2016). Maternal inflammation can also increase oxidative stress in the fetal brain by increasing the number of reactive oxygen species molecules that harm cells in the brain and interfere with neuronal connections (Mannaerts et al., 2016). Lastly, inflammation may also alter gene expression in brain regions core to cognition and emotion regulation, thereby altering their developing size and function (Gyllenhammer et al., 2022). Maternal gestational weight gain (GWG): excessive maternal GWG has been linked to several mechanisms underlying adverse fetal cognitive and emotional development. First, maternal obesity may lead to the dysregulation in the expression of hormones such as insulin and leptin in brain regions such as the limbic system and cortex, regions heavily involved in cognition and ER (Hasebe et al., 2021). Abnormal insulin and leptin signaling in the fetal brain may also lead to poor neuronal differentiation and development (Valleau et al., 2014). Second, maternal obesity may interfere with the development of serotonergic and dopaminergic systems that have been implicated in many neurodevelopmental disorders (Shook et al, 2020). Reduced serotonin synthesis may impact neuronal processes such as neurogenesis and neuronal migration, Ph.D. – N. Mortaji; McMaster University–Neuroscience 17 as well as the initial development of the central nervous system (Hwang et al., 2019). Similarly, dysregulation of the dopaminergic system can lead to altered expression and signaling of dopamine in brain regions such as the PFC and lead to reduced synaptic connections between the PFC and other regions key in cognition and ER (Hanswijk et al, 2020). Lastly, maternal obesity is characterized by chronic inflammation throughout pregnancy which can adversely affect oxidative stress, expression of pro-inflammatory cytokines and reduced neurotrophic levels in the fetal brain (Parisi et al., 2021). Maternal infection: an infection during pregnancy may have direct and indirect effects on cognitive and ER development in the fetus. Directly, maternal infection may impair cells in brain regions and cause significant changes to the function and structure of these regions (Jash et al., 2022). Indirectly, maternal infection may lead to placental aberrations and reduce the delivery of nutrients and oxygen available to the fetal brain (Estes et al., 2016). Additionally, infection may lead to an increase in maternal inflammatory cytokines which are particles that disrupt brain cell formation (Elgueta et al., 2022). Maternal distress: maternal distress refers to feelings of stress, depression and anxiety can alter fetal brain structure (Wu et al., 2022). Since maternal distress is characterized by elevated levels of glucocorticoids that may enter the fetal brain through the placenta, it may impact neurotransmission and cell structure of regions important to cognition and ER (Miranda et al. 2018). Additionally, maternal distress is associated with white matter changes in the fetal brain, which are important for neuronal communication between brain regions and synaptic formations (Demers et al., 2021). White matter structures begin to develop in the second trimester and the majority of its structures are developed by birth (Wilson et al., 2021). Therefore, maternal distress may compromise white matter integrity during a period where it is Ph.D. – N. Mortaji; McMaster University–Neuroscience 18 rapidly developing and forming connections between key cognitive and ER circuits (Martínez- García et al, 2021). 2.2 Postnatal Determinants The postnatal environment introduces a variety of experiences and stimuli that are important for rapidly developing brain, and that can interact with postnatal factors to shape cognition and behaviour. The home environment: the home environment provides infants and children with exposures to many factors that influence cognitive and ER development. First, the quality of caregiver relationships can directly shape ER abilities in infants and children (Karakas et al., 2019). Responsive and predictable caregivers promote the development of secure attachment styles in their children which will promote a healthy stress response (Benoit et al., 2004). Second, the availability of resources and stimulation for the child such as playing, reading, and providing a variety of toys may enable their cognitive development by forming and improving neural connections between cognitive brain regions such as the hippocampus and PFC (Gee et al, 2021). Socioeconomic status (SES): children raised in households marked by socioeconomic disadvantage may also be at risk for poorer cognitive and ER development (Blair et al., 2016). Lower SES may influence the quality of stimulation and support available to the child (Schmidt et al, 2021), and since stimulation and support from caregivers is important for the development of cognitive-based neural circuits, lower SES may have a negative impact on cognitive development (Noble et al., 2015). Additionally, lower SES has been linked in studies with additional challenges such as abuse and familial disharmony. These exposures can negatively Ph.D. – N. Mortaji; McMaster University–Neuroscience 19 impact ER development by causing an overactive stress response and deficits in brain regions such as the amygdala (Johnson et al., 2016). Additionally, the chronic exposure to these challenges can lead to problems with anxiety and depression in children that may impact their ER development and abilities (Franke et al., 2014). Child diet/breastfeeding: Breastfeeding in infancy has also been linked to cognitive and emotion regulation development in children. Breastmilk provides essential nutrients such as long-chain polyunsaturated fatty acids that are only found in breastmilk and can improve cognitive development (Krol et al., 2018). Breastfeeding may also improve emotion regulation development by promoting a secure attachment style between mother and infant and increasing hormones such as oxytocin that promote bonding necessary for secure attachments (Bigelow et al., 2022). Similar to prenatal diet, an overall healthy child diet is required to continue the development of brain regions and neuronal connections between regions key to cognition and ER (Irvine et al., 2022). 3. Modifiable lifestyle interventions and offspring cognitive and ER development 3.1 Nutrition during pregnancy Following nutritional recommendations during pregnancy is important for both fetal and maternal health. The current nutritional recommendations for pregnant people include guidance on caloric intake, as well as that of key vitamins and minerals, macronutrients and weight gain (Jouanne et al., 2021). Since pregnancy produces extra demands on the body, it is recommended that pregnant people consume an additional 350 calories per day starting in the second trimester and increasing calories by 500 in the third trimester per fetus (Kominarek et al., 2016). Consuming a variety of vitamins and nutrients is important for optimal fetal brain development, Ph.D. – N. Mortaji; McMaster University–Neuroscience 20 therefore, a prenatal multivitamin supplying all key vitamins and minerals needed during pregnancy is crucial. Deficits in vitamins or minerals, or too much of certain vitamins can be harmful to fetal brain development (Mousa et al., 2019). For example, folic acid is a vitamin that is essential for the development of the fetal spine and brain. However, the recommended dosage of folic acid (600 micrograms) during pregnancy is difficult to obtain from food alone, and so a prenatal supplement is often recommended for the prevention of neural tube defects (Balashova et al., 2018). Additional vitamins that are required for a healthy pregnancy and fetus include iron (27 milligrams), calcium (1000 milligrams), iodine (220 micrograms), choline (450 milligrams), vitamin C (85 milligrams), vitamin D (600 international units) and omeg-3 fatty acids (200 milligrams) (Brown et al., 2020). In addition to vitamins and minerals, macronutrient consumption, specifically protein intake is crucial to infant brain development during pregnancy (Mousa et al., 2019). Protein provides the amino acids that comprise fetal cells and is especially important in the second and third trimester as the fetal brain is rapidly developing (Murphy et al., 2021). Protein intake recommendations during pregnancy consist of 20-25% of caloric intake (Herring et al., 2018). It is important that a combination of micronutrients and macronutrients be consumed during pregnancy to receive the range of benefits they offer fetal brain development. Lastly, to ensure a healthy and safe pregnancy for both the mother and the fetus, and reduce complications throughout pregnancy, appropriate GWG is recommended. the recommended GWG during pregnancy is dependent on weight prior to conception. For example, underweight woman (BMI <18.5 kg/m2) are recommended to gain more weight during pregnancy than normal weight woman (BMI 18.5-24.9 kg/m2), and overweight/obese woman (BMI >25 kg/m2) are recommended to gain less weight (Sun et al., 2020). The recommended Ph.D. – N. Mortaji; McMaster University–Neuroscience 21 GWG guidelines for normal weight woman are half-pound to 1 pound per week from the second trimester to the end of pregnancy (Gilmore et al., 2015). These values increase or decrease if woman are underweight or overweight/obese respectively. 3.1.2 Studies examining maternal nutrition and offspring cognitive and ER development and their limitations Maternal nutrition and offspring cognitive and ER development have been extensively reviewed in the literature. Decades of observational studies have found links between maternal nutrient intake and cognitive and ER development. For example, higher maternal choline intake has been associated with impaired executive function, verbal and visual memory, memory and attention, lower risk of attention-deficit / hyperactivity disorder (ADHD), and better HRV from 3 months of age to 7 years of age (Boeke et al,. 2013; Pugh et al., 2016; Fuemmeler et al., 2019). Greater maternal omega-3 fatty acid intake has been associated with better problem solving and language abilities, improved planning and organization skills, and improved HRV from 2 months of age to 8 years of age (Baumann et al., 2018; Christensen et al., 2011; Jackson et al., 2018). Other studies have examined the associations between greater maternal fruit and vegetable intake during pregnancy and reduced hyperactivity and aggression, and better receptive and expressive language in children aged 2 to 7 years of age (Murphy et al., 2014; Polanska et al., 2021; Miyake et al., 2020) . In terms of macronutrient consumption during pregnancy, studies have found associations between higher maternal protein intake and language development, problem solving skills, better HRV, and less hyperactivity and aggression in 6 months olds to 3 year olds (Taylor et al., 2021; Mahmassani et al., 2022; Wang et al., 2021). However, two major limitations exist in the literature of maternal nutrition and offspring neurodevelopment. First, the majority of studies examining maternal nutrition and child neurodevelopmental outcomes have examined single Ph.D. – N. Mortaji; McMaster University–Neuroscience 22 nutrients (as opposed to overall diet) which is not representative of human diets. Since nutrients do not act in isolation, but synergistically, good overall diet quality provides various benefits from the consumption of different micro and macronutrients, and thus has the ability to maximize fetal and child neurodevelopmental outcomes (Cheatham et al, 2015). Additionally, overall diet quality may improve maternal health outcomes such as prevention of GDM, obesity, and hypertension (all of which adversely affect fetal neurodevelopment), while single nutrients are limited in their ability to do so (Dierlein et al., 2021). Second, most of the studies in the literature are observational in nature and limit our ability to establish causal relationships. Since diet quality is modifiable, and easily implementable during pregnancy, RCTs examining overall diet quality and offspring neurodevelopment are extensively needed to bridge the gap between the complex interactions between nutrients and their effects on fetal neurodevelopment. 3.2 Exercise during pregnancy Exercise during pregnancy may offer multiple additive benefits to maternal and fetal health if performed safely. The current exercise guidelines recommend 150 minutes of moderate- intensity aerobic exercise weekly (Yang et al., 2019). Although walking is the safest and most recommended form of exercise, other exercises may include swimming, yoga, or activities such as gardening (Bull et al., 2022). However, less than 15% of pregnant woman follow the recommended guidelines for exercise due to the fear of exercise related complications during pregnancy (Connell et al., 2021). Research suggests that exercise during pregnancy has not been associated with adverse pregnancy complications, rather, exercise has prevented or improved pregnancy complications such as obesity, GDM, hypertension, and fetal neurodevelopmental outcomes (Parikh et al., 2021). Exercise intensity should be reduced as pregnancy progresses, specially in the third Ph.D. – N. Mortaji; McMaster University–Neuroscience 23 trimester as fetal demands have increased and require greater oxygen delivery (Beetham et al., 2019). Although exercise offers numerous benefits during pregnancy, it is important to discuss exercise plans with health care professionals as there are certain contraindications to exercise such as woman with pre-eclampsia, pregnancies with more than one fetus (twins, triplets), or have placenta previa in the third trimester (Evenson et al., 2014). 3.2.1 Studies examining maternal exercise and offspring cognitive and ER development and their limitations Research examining the effects of maternal exercise on fetal and child cognitive and ER outcomes is limited. Observational studies have reported links between women who exercise during pregnancy and child cognitive outcomes such as improved attention, working memory, executive function, and language abilities from 4-5 years of age, compared to non-exercising woman (Robinson et al., 2012; Di Liegro et al., 2019; Dalile et al., 2022). Observational studies have also reported pregnancy exercise is associated with improved emotion regulation abilities such as better self-soothing abilities, self-control, fewer negative emotions, and more positive affect in 6 month to 5 year olds compared to non exercising woman (Penner et al., 2022; Zhang et al., 2019). The majority of RCTs examining exercise and child emotion regulation utilize HRV as the only measure of ER. Two RCTs reported women who performed moderate-intensity aerobic exercise had offspring with better HRV at 1 month (May et al., 2013) and 1 year of age (May et al., 2014). However, fetal HRV can also be measured during gestation using fetal electrocardiography, and RCTs have reported improved fetal HRV from 28 to 35 weeks gestation in response to maternal exercise (Bauer et al., 2020). Nonetheless, limitations in the field of pregnancy exercise and offspring neurodevelopment still exist. First, very few RCTs have been conducted, limiting our understanding of causality. Second, the majority of studies have used Ph.D. – N. Mortaji; McMaster University–Neuroscience 24 only a single physiological measure to measure ER (HRV) which is not a comprehensive and recommended approach to measuring ER. Therefore, RCTs using multiple approaches to test offspring cognition and ER are still needed. Additionally, maternal exercise has not been examined in combination with other modifiable risk factors such as maternal nutrition to improve offspring neurodevelopment. Since maternal nutrition and exercise are both modifiable and easily implementable during pregnancy, it may be important to examine their synergistic benefits on offspring neurodevelopment. 3.3 Potential synergistic effect of nutrition + exercise While observational studies examining the impact of pregnancy nutrition and exercise on child cognition and ER are extremely rare, no RCTs examining these effects exist. One observational study reported that infants who had mothers that exercised during pregnancy and took an omega-3 fatty acid supplement had better cognitive scores such as language scores at 1 and 6 months of age, compared to infants born to women who only exercised or only took an omega-3 supplement (Braarud et al., 2018). However, the combination of good nutrition and exercise during pregnancy offers many maternal and fetal benefits. First, women are more likely to achieve the recommended GWG, and reduce the risk of pregnancy complications such as GDM, hypertension, inflammation, and obesity if they consume a healthy diet and exercise (Lewandowska et al., 2020). These complications may also lead to adverse development of the fetal brain (Zheng et al., 2019). Second, the combination of good nutrition and exercise during pregnancy may lead to better postpartum health and recovery. Pregnant people who combine a healthy diet and exercise report better mood during postpartum, such as less anxious and depressive symptoms, and return to pre- pregnancy weight faster (Evenson et al., 2014). These effects can have important implications for Ph.D. – N. Mortaji; McMaster University–Neuroscience 25 infant cognitive and emotional development as maternal mood disorders have been linked to poorer child cognitive and ER development during the early postnatal period (Slomian et al., 2019). Lastly, since maternal nutrition provides important nutrients required for fetal brain development, and maternal exercise improves the placental delivery of these nutrients to the fetus, the combination of nutrition and exercise ensures optimal absorption of nutrients (Sebastiani et al., 2019). Therefore, the synergistic effects of maternal nutrition and exercise throughout pregnancy can potentially create a ceiling effect, where the fetus has the most optimal prenatal conditions to grow and develop, whereas without one of these conditions the foundation for optimal fetal brain development may be comprised. 3.4 The importance of modifiable prenatal factors Since brain plasticity decreases with age, prenatal interventions represent the most efficient and effective means by which child cognition and ER can be optimized (Oberman et al., 2013). Further, even economists have reported that investments in the development of fetal and early child outcomes are one of the most cost-effective public expenses (Bono et al., 2016). Additionally, a growing body of evidence has shown that improving prenatal factors (i.e., nutrition and exercise) during pregnancy may have protective effects against postnatal adversity (Moyer et al., 2016; Cattane et al., 2021). By optimizing fetal brain development and creating an optimal foundation for brain development postnatally, offspring may be more resilient to postnatal adversity. Longitudinal studies have also supported that improving prenatal factors such as nutrition, exercise, stress and exposure to toxins can improve cognition and ER from infancy into adolescence, suggesting the long-lasting benefits of improved prenatal conditions (Campbelle et al., 2012; Lumey et al., 2011; Eskenazi et al., 2006). In order to reduce the risk of Ph.D. – N. Mortaji; McMaster University–Neuroscience 26 early cognitive and ER problems, and reduce the economical costs to correct such problems, improving modifiable prenatal factors is of great importance. 3.5 Lifestyle interventions during pregnancy and their potential to improve maternal and fetal/child health Lifestyle interventions such as nutrition and exercise interventions are ideal for optimizing child cognition and ER for several practical reasons. First, women are most motivated to make healthy changes during pregnancy than at any other time in their lives (Bagherzadeh et al., 2021). Second, this is a time when women regularly interact with healthcare providers, increasing compliance of such interventions (Sword et al., 2012). Third, women prefer lifestyle to pharmacological treatments (including herbal supplements) (Jarbol et al., 2017). Fourth, women may be more able to fully engage in interventions prenatally as opposed to after delivery (Sword et al., 2012). Fifth, significant public health infrastructure exists in Canada to deliver programming related to prenatal nutrition (Canada Prenatal Nutrition Program). Finally, cognitive and self-regulatory problems are important precursors to substance use disorders and school problems, two of parents' most significant concerns for their children (Griffen et al., 2010). However, although prenatal nutrition and exercise interventions hold immense promise for improving maternal and fetal outcomes, there are a lack of studies examining the combined effects of nutrition and exercise on fetal cognition and ER using RCTs. Since prenatal factors have shown to lead to improved cognitive and ER outcomes in children, they could provide the scope for the primary prevention or amelioration of cognitive and ER problems early in life. Additionally, investigating the impact of prenatal factors such as nutrition and exercise on cognition and ER would enable us to further test the preventative potential of the DOHaD hypothesis by examining the plasticity of brain regions and systems core to cognition and ER. Ph.D. – N. Mortaji; McMaster University–Neuroscience 27 References Al Aboud, N. M., Tupper, C., & Jialal, I. (2022). Genetics, Epigenetic Mechanism. In StatPearls. StatPearls Publishing. Arioli, M., Crespi, C., & Canessa, N. (2018). 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Context and Implications of this study: The first study examined the effects of prenatal diet quality on Executive function (EF) and/or behavioral development in children raised in suboptimal home environments. Maternal diet quality is a modifiable risk factor during pregnancy that has not been extensively examined in relation to offspring ER and behaviour, which may limit our understanding of the preventative potential of the DOHaD hypothesis. This was the first study to show the positive associations between a prenatal exposure (maternal diet quality) in the presence of increased postnatal adversity. We found that healthier maternal diet quality appears to potentially benefit child EF and behavioural development in children from suboptimal home environments. Acknowledgements: We thank the Mother-Infant Research on Environmental Chemicals (MIREC) Study Group as well as the MIREC study participants and staff. Conflicts of interest: None Published in: American Journal of Clinical Nutrition 2021; 00:1–10 Ph.D. – N. Mortaji; McMaster University–Neuroscience 39 Abstract Background: Optimal maternal nutrition during pregnancy has been linked to better cognitive and behavioral development in children. However, its influence on the effects of suboptimal postnatal exposures like reduced stimulation and support in the home is not known. Objectives: To examine the effect of maternal pregnancy diet on executive function and/or behavioral development in children raised in suboptimal home environments. Methods: Data were provided by 808 mother–infant dyads from the Canadian Maternal-Infant Research on Environmental Chemicals–Child Development study. Maternal pregnancy diet was self-reported using the Healthy Eating Index 2010 questionnaire. Stimulation and support in the home was assessed using the Home Observation for Measurement of the Environment (HOME) when children were 3–4 y old. Child executive function was reported by mothers at this age using the Behavior Rating Inventory of Executive Functioning–Preschool Edition, and child behavior was assessed using the Behavior Assessment System for Children–2nd Edition. We examined the interaction of maternal pregnancy diet and postnatal HOME scores on child executive function and behavior using linear regression adjusted for maternal education, postpartum depression, pre-pregnancy BMI, and smoking. Results: Maternal pregnancy diet was associated with an increasingly positive association with child working memory (β: 0.21; 95% CI: 0.82, 3.41; P = 0.001), planning (β: 0.17; 95% CI: 0.38, 2.84; P = 0.007), and adaptability (β: –0.13; 95% CI: –1.72, –0.08; P = 0.032) as levels of postnatal stimulation decrea