Neurodevelopmental Pediatrics: Genetic and Environmental Influences

Preface
Acknowledgment
Contents
Contributors
Part I: Overview of CNS Development and Disorders
	1: Overview of CNS Organization and Development
		Introduction: Brain Development
		Types of Neurons
		Neurochemical Signaling Molecules and Their Receptors in Brain Development
			Neurotrophic Factors
			Neurotransmitters
			Neuropeptides and Peptide Hormones
			Steroid and Thyroid Hormones
			Chemokines and Cytokines
		Synapses and Neural circuits
			Synapses
			Neural Circuits
		Glial Cells and Brain Development
			The Tripartite Synapse and Gliotransmitters
		Development of the Neuroendocrine System: The Hypothalamic-Pituitary System
			The Hypothalamus
			The Pituitary Gland
			The Neuroendocrine System and Neurodevelopmental Disorders
		Development of the Neuroimmune System
			The Neuroimmune System and NDD
		Signaling Molecules as Epigenetic Transducers: Converting Environmental Signals to Gene Expression and Protein Synthesis
		Critical (Sensitive) Periods in Development
			Puberty as a Critical Period in Brain Development
			Critical Periods and Neurodevelopmental Disorders
		Summary
		References
	2: Neural Induction and Regionalization
		Introduction to the Neural Tube and Early Regionalization of the Central Nervous System
		Neural Induction
			Model Systems: Drosophila, C. Elegans, Xenopus, Chick, and Mouse
			Setting Up Anterior/Posterior and Dorsal/Ventral Axes
			Nodes and Organizers
			Inducers, Morphogens, Gradients, and Signaling Pathways
				Retinoids
				Vertical Versus Planar Neural Induction
		Lateral Inhibition and Notch Signaling
		Asymmetric Versus Symmetric Cell Divisions
			Radial Versus Tangential Migration
			Induced Pluripotent Stem Cells (iPSC)
			Three-Dimensional (3D) Central Nervous System Organoids
		Disorders of Neural Induction, Early Regionalization, and Patterning
			Holoprosencephaly
			Anencephaly and Other Neural Tube Defects
			Lissencephaly, a Neuronal Migration Disorder
			Hydrocephalus
		References
	3: Neural Stem Cells, Differentiation, and Migration
		Introduction
		Building the Central Nervous System
			Embryonic Neural Stem Cells, Migration, and Differentiation
		Neural Stem Cell Heterogeneity
		Neurogenic Niches
			The Subependymal Zone
			The Subgranular Zone
			The Periventricular Zone
			Regulating the Neurogenic Niche: Sex, Age, and Injury
		Neural Stem Cells in Regenerative Medicine
			Exogenous Stem Cell-Based Approaches
			Endogenous Stem Cell-Based Approaches
			Obstacles, Challenges, and Considerations
		Summary and Conclusions
		References
	4: Neurotrophins and Cell Death
		Developmental Cell Death and Brain Development
		Neurotrophins
			Neurotrophins and their Receptors
			Downstream Signaling
		Pro-Neurotrophins
			Pro-Neurotrophin Receptors and Downstream Signaling
			NGF, proNGF, and Neuronal Refinement
		Neurotrophins and Development
			NGF
			BDNF
				BDNF, Activity-Dependent Expression, and Dendritic and Axonal Arborization
				BDNF and Synapse Development
				BDNF and Synaptic Plasticity
			NT-4
			NT-3
		Parallels in the Adult Brain
			Neurogenesis
		BDNF and Neurodevelopmental Disorders
			Autism Spectrum Disorder
			Epilepsy
			Fetal Alcohol Spectrum Disorder
		Summary
		References
	5: Synaptogenesis
		Overview of the Structure of Synapses in the Central Nervous System
			The Presynaptic Compartment
			The Postsynaptic Compartment
		Astrocytes: A Third Compartment at the Synapse
		Synaptogenesis
			Initial Contact
			Synapse Assembly
			Neuronal and Glial Secreted Molecules in Synaptogenesis
		Synapse Remodeling and Elimination
			Role of Glia in Synapse Elimination
		Altered Excitatory/Inhibitory Balance in Neurodevelopmental Disorders
		Conclusion
		References
	6: Axonal Guidance
		Introduction
		The Growth Cone
		Role of the Substrate: Adhesive Guidance and Labeled Pathways
			Intermediate Targets Simplify the Journey
		Robo/Slit Signaling Prevents Commissural Axons from Recrossing the Midline
		Semaphorin/Plexin/Neuropilin Signaling
			Class 3 Semaphorins Help to Expel Commissural Axons from the Floor Plate
		Ephrin/Eph Signaling
			EphrinBs and EphAs Constrain Non-Crossing Axons in the Spinal Cord
			Mapping of Retinal Axon Projections by EphrinA Signaling
		Netrins
			Netrins Attract Commissural Axons to the Midline
		Response-Switching Regulatory Mechanisms
		Regulatory Mechanisms Not Involving Changes in Receptor Expression in the Growth Cone
		Intracellular Signaling in the Growth Cone
		Axon Guidance in Human Disease
		Axonal Regeneration
		Summary
		References
	7: Myelination
		Introduction
		Myelin: Structure and Function
			Function
			Structure
		Myelinogenesis
		Oligodendrocytes: Development and Function
			Oligodendrocyte Function
			Development of the Oligodendrocyte Lineage
			Oligodendrocytes in the Adult CNS
			Genes Implicated in Oligodendrocyte Development
				Olig Genes
				Plp1
				Mbp
				Cnp
				PDGFRa
		Mouse Models
			Olig1-Null Mice
			Jimpy
			Rumpshaker
			Shiverer
		Disorders of Myelination
			Leukodystrophies
			Autoimmune Disorders
		Remyelination and Rehabilitation Medicine
			Remyelination
			Remyelination Failure
			Regeneration/Therapeutic Approaches to Restore Myelin
				Transplantation of Exogenous OPCs
				Promotion of Endogenous Remyelination
		Conclusion
		References
	8: Epigenetics
		Introduction
		Epigenetic Mechanisms
			Chromatin and Histones
				Chromatin Remodeling
				Histone Variants
				Histone Posttranslational Modifications
			DNA Modifications
				DNA Methylation
				DNA Hydroxymethylation
			RNA Modifications
			Noncoding RNAs
				Small Noncoding RNAs
				Long Noncoding RNAs
			Conclusions
		Epigenetics of Neurodevelopment
			Preconception, Fertilization, and Early Embryogenesis
			Neural Tube Formation and Neurogenesis
		Structuring of the Brain Architecture
		Epigenetic Regulation of Synapses
		Balance Between Proliferation and Neuronal Cell Death
		Gliogenesis and Myelination
		Epigenetic Dysregulation and Neurological Disorders
		Epigenetic Embedding of EarlyLife Influences
		Tools and Techniques to Study Epigenetics
			Model Organisms and Human Populations
			DNA Modification Studies
				Epigenetic Clocks
				Cell Type Specificity
			Chromatin Studies
			RNA Studies
			Multiomics
		Conclusion
		References
	9: The Impact of an Adverse Intrauterine Environment on Neurodevelopment
		Section 1: An Adverse Intrauterine Environment
			Chorioamnionitis (CHORIO)
			Progression of Chorioamnionitis
			Chorioamnionitis and Preterm Labor
			Chorioamnionitis and Term Birth
			Placental Insufficiency and Intrauterine Growth Restriction
		Section 2: Fetal Inflammatory Response Syndrome and Systemic Inflammatory Response Syndrome
			Progression of FIRS
			Funisitis Develops Concomitantly with FIRS
			Systemic Inflammatory Response Syndrome
		Section 3: Sustained Peripheral Immune Hyperreactivity
			Evidence for SPIHR
			Peripheral Inflammation Infiltrates the CNS
			CNS Immune Response – Neuroinflammation
			Sustained CNS Inflammation
		Section 4: Neonatal Brain Injury
		Section 5: Long-Term Outcomes
			Cerebral Palsy
			Posthemorrhagic Hydrocephalus Secondary to Intraventricular Hemorrhage
			Cognitive Impairment/Executive Dysfunction
		Chapter Summary
		References
	10: Stress as a Determinant of Neurodevelopmental Outcomes
		Outcomes
			Altered HPA Axis Function
			Altered Attention (ADHD Symptomology)
			Affective Disorder (Internalizing/Externalizing Behaviour (Depression/Anxiety))
			Cognitive Impairment
		Mechanisms
			Brain Structure
			Serotonin
			Inflammation
			Placental 11β-Hydroxysteroid Dehydrogenase 2 (11β-HSD2)
			Genetic and Epigenetic Mechanisms
			Paternal Influence
		Conclusion
		End-of-Chapter Summary
		References
	11: Sex Differences in Neurodevelopment and Its Disorders
		Introduction to Sex Differences in Neurodevelopmental Disorders
		Sex Determination and Sexual Differentiation
			Genetic and Epigenetic Disorders of Sex Determination
			The Neurobiology of X-Linked Intellectual Disabilities and Infectious Diseases
		Sexual Differentiation of the Brain
			Genetic and Epigenetic Factors in Brain Sexual Differentiation
			Genes, Hormones, and Microglia Interact in the Sexual Differentiation of the Brain
			Sexual Differentiation of Glial Cells: Astrocytes and Microglia
		Sex Differences in the Brain
			Neuroanatomy
			Neural Circuits
			Neurochemistry
			Summary: Sex Differences in Brain Structure, Function, and Neurochemical Pathways
		The Role of Glial Cells in the Sexual Differentiation of the Brain
			The Role of Glial Cells in Sex Differences in NDD
			Gut Microflora, the Immune System, Glial Cells, and Sex Differences in NDD
		Sexual Differentiation of the Hypothalamic-Pituitary (Neuroendocrine) System
			Neurohypophyseal Hormones and Sex Differences in NDD
			Adenohypophyseal Hormones, Sex Differences, and NDD
				HPG System
				HPA System
				The HPT System
				GH and Prolactin
			Summary and a Caveat
		Puberty: The Organization of the Adult Brain and the Integration of Sex Differences in the Neuroendocrine, Neuroimmune, and Energy Homeostasis Systems
			Puberty-Related Neural and Neuroendocrine Reorganization
			Sex Differences in Microglia at Puberty
			Sex Differences in Gene Expression at Puberty: Epigenetic Effects of Gonadal Hormones
			Summary
		Puberty-Related Neurodevelopmental Disorders
			Disorders of Puberty Timing
			Sex Differences in the Activation of Reward Pathways at Puberty: Eating Disorders and Addictions
			Sex Differences in Neuropsychiatric Disorders, Anxiety, and Depression at Puberty
			Disorders/Differences of Sexual Development
		Summary: Theories About the Causes of Sex Differences in Neurodevelopmental Disorders: Genetic, Hormonal, Immune, and Environmental (epigenetic) Mechanisms
		References
Part II: Autism Spectrum Disorders
	12: The History of Autism Spectrum Disorder
		Introduction
		Early Definitions of Autism
		Child and Adolescent Psychiatry as an Emerging Field
		Applying Psychoanalytic Theories to Understand Childhood Schizophrenia
		Categorizing and Classifying to Understand Childhood Schizophrenia
		Autism Emerging as a Distinct Disorder
		Differentiating Between Autism as an Intrinsic Condition Vs. Autism as Experientially Derived
		Applying an Empirical Behaviourist Approach to Understand Autism
		Exploring Autism as a Language Disorder
		Exploring Autism as a Social Cognition Disorder
		Early Understandings of Autism as a Neurobiologic Condition
		Looking Back: Possible Early Accounts of Autism in our Histories
		Other Social and Cultural Factors Shaping Views of Autism
		Conclusion
		Considering Historical Figures: Spotlight on Bruno Bettelheim
		Considering Historical Figures: Spotlight on Hans Aspergers
		Considering Historical Figures: Spotlight on Bernard Rimland
		References
	13: Epidemiology
		Introduction
		International Policy Context
		Epidemiological Estimates
			Case Definition
			Case Finding
			Case Identification and Evaluation
			Cultural Considerations in Case Definition and Evaluation
		Risk Factors Vs. Social Determinants
			Sex
			Demographics
			Socioeconomic Status
			Race/Ethnicity and Nativity
		Time Trends
		Conclusion
		References
	14: An Approach to the Diagnosis of Autism Spectrum
		Introduction
		History Taking
		Collateral Information
		Observation and Interaction
		Standardized Testing
		Physical Examination
		Allied Health Assessments
		Diagnostic Feedback
		Family Preferences
		Cultural Considerations
		References
	15: Autism Spectrum Disorder: Cognition
		Introduction
		Theories of Autism Spectrum Disorder
		Attention
		Perception
		Intelligence, Academics, and General Cognition
		Memory
		Executive Functioning
		Social Cognition
		Language
		Limitations and Future Directions
		References
	16: The Neuroradiology of Autism: Framing Neuroimaging Investigations of the Autistic Brain Based on the US NIMH Research Domain Criteria
		Introduction
		Neuroimaging Findings Based on RDoC Domains
			Negative Valence Systems
			Positive Valence Systems
			Cognitive Systems
				Attention, Cognitive Control, and Working Memory
				Perception
				Language
				Summary of Cognitive Systems
			Social Processes Systems
			Arousal and Regulatory Systems
			Sensorimotor Systems
		Caveats in Current Understanding and Future Perspectives
			Developmental and Environmental Influences
			Heterogeneity
			Understudied Populations
			Imaging Methodology
			Measuring Idiosyncrasy
			Searching for Biomarkers
		Conclusion
		References
	17: Neuropathology of Autism
		Introduction
		Whole Brain Alterations
		Alterations Consistently Found by Region
			Cortical Alterations
			Cerebellar Alterations
			Amygdala Alterations
			Brainstem Alterations
		Immunologic-Driven Alterations
		Animal Models of ASD and Related Neuropathological Alteration
			A Short Briefing on Genetics
			Fragile X Mental Retardation Gene (FMR1)
			Tuberous Sclerosis complex1/2 Genes (TSC1/2)
			Methyl-CpG-Binding Protein 2 (MECP2)
			SH3 and Multiple Ankyrin Repeat Domains 3 Gene (SHANK3)
			Neurexins (NRXN)
			Neuroligins (NLGN)
			Chromodomain Helicase DNA-Binding Protein 8 (CHD8)
			Synaptic GTPase-Activating Protein 1 (SynGAP1)
			AT-Rich Interactive Domain Containing Protein 1B (ARID1B)
			Glutamate Receptor Ionotropic, NMDA 2B (GRIN2B)
			T-Brain-1 (TBR1)
		Final Considerations
		References
	18: Genetics and Epigenetics of ASD
		Introduction
		Genetic Etiology
			Genetic Heritability of ASD
			Genomic Architecture of ASD
			From ASD Candidate Gene to Candidate Pathways
				Regulation of Gene Expression Mechanisms
					Epigenetics and Chromatin Remodeling
					Transcription Factors
					Alternative Splicing
					MicroRNA Gene Expression
				Synaptic and Signaling Pathways
					Synaptic Development and Altered Neural Circuit
					GABA- and Glutamate-Mediated Neurotransmission
			Environmental Factors
				Maternal Gestational Environment
				Parental Age
				Gut Microbiota
				Sex-Specific Traits and Gene–Environment Interactions
		Conclusion
		End-of-Chapter Summary
		References
	19: Preclinical Models of Autism Spectrum Disorder
		Introduction
		Modelling ASD in Animals
			Genetic Models
			Environmental Models
			Animals Used to Model ASD
		Methods for Assessing Animal Models
			Behavioural Assessments
			Molecular-Anatomical Methods
			Functional-Anatomical Methods
		Findings from Preclinical Studies
			Neurobiology and Neuroanatomy
			Treatment Discovery
		Conclusions
		References
	20: Biomedical Interventions for Autism Spectrum Disorder
		Introduction
		Where We Have Evidence for Effective Medications (Table 20.1)
			Irritability
		Attention-Deficit Hyperactivity Disorder (ADHD) Symptoms
		Repetitive Behaviors
		Anxiety and Depression
		Seizures
		Sleep
		Complementary and Alternative Medicine
		Research Directions
		References
	21: Interventions in ASD: Psychosocial Interventions and Supports for ASD
		Introduction
			Behavioural (ABA-Based) Intervention
				ABA-Based Intervention in the Preschool and Early School Years
				Parent Involvement in ABA-Based Programs
			Naturalistic Treatment Approaches for Young Children
				Naturalistic Developmental Behavioural Intervention (NDBI)
				Developmental and Social-Pragmatic Intervention Models
			Intervention Approaches for Toddlers
				‘Packaged’ Parent-Implemented Interventions for Toddlers
			Group-Based Social Skills Interventions
			Educational and Other School-Based Supports
				Academic and Learning Supports
				Other School-Based Interventions
				Post-Secondary Education
			Mental Health Supports
			Behavioural Interventions for Disruptive Behaviour Challenges
		Conclusions
		References
Part III: Fetal Alcohol Spectrum Disorder
	22: Clinical Perspectives on the Diagnostic Assessment of Individuals with FASD
		Introduction
		Confirmation of Prenatal Alcohol Use
		Symptoms of FASD across the Lifespan
			Common Symptoms in Infancy
			Common Symptoms in Preschoolers
			Common Symptoms in School Age
			Common Symptoms in Adolescents
			Adults with FASD
		Diagnostic Process and Multidisciplinary Assessments
			Medical Assessment
			Assessment of FASD Dysmorphology
			Multidisciplinary Neurobehavioral Assessment
		Case Example of FASD Diagnostic Assessment by Age
			Case Example: April
				Referral History
			Social Background
			Prenatal Alcohol/Drug Exposure History
			Maternal/Neonatal History
			Medical and Family History
			Developmental History
			Physical Assessment
			Neurodevelopmental Assessments
				Psychological Assessment
			Occupational Therapy Assessment
			Speech Language Assessment
			Final Diagnoses
			Clinical Suggested Recommendations
			Adolescent Follow-Up
		Final Comments/Summary
		References
	23: Epidemiology of Alcohol Consumption among Pregnant and Childbearing Age Women and Fetal Alcohol Spectrum Disorder
		Prevalence of Alcohol Use among Childbearing-Aged Women
		Alcohol Use during Pregnancy
		What Is Fetal Alcohol Spectrum Disorder?
		Prevalences of Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorder (FASD) in the General Population
		FASD Prevalence in Sub-Populations
		Conclusion
		References
	24: Fetal Alcohol Spectrum Disorder: Diagnosis
		Introduction
		Epidemiology and Cost of FASD
		Importance of Early Diagnosis
		Background and Terminology for the Diagnosis of Fetal Alcohol Spectrum Disorder
		Terminology Associated with Diagnosis
		Diagnosis
		The Diagnostic Process
			Confirmation of Prenatal Alcohol Exposure
		Prenatal Alcohol Exposure and the Developing Fetus
		Confirming Maternal Alcohol Exposure
		Biomarkers
		The Physical Examination and Differential Diagnosis
			Facial Features
			The Neurobehavioural Assessment
				Diagnostic Criteria from the Canadian Guidelines
				FASD and Mental Health
				Imaging as a Diagnostic Tool
		Treatment and Follow-Up
		Specific Populations
			FASD Diagnosis in Infants
			FASD Diagnosis in Adults
		Conclusion
		References
	25: Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorder (FASD)
		Introduction
		Quantitative MRI findings in FASD
			Brain structure in FASD
		Brain Function in FASD
		Brain Development in FASD
		Newer Techniques
		Links to Cognition and Behaviour
		Future Directions
		Conclusions
		References
	26: Neuropathological Changes in Humans with History of Prenatal Alcohol Exposure or Diagnosis of Fetal Alcohol Spectrum Disorder
		Introduction
		Review of PNAE/FASD Neuropathology
		Discussion
			Alcohol Dose and Multiple Substance Abuse
			Microencephaly
			Neural Tube Defects
			Vascular Damage
			Corpus Callosum Anomalies
			Hydrocephalus
			In Utero and Neonatal Infections
			Shortcomings of Autopsy Studies
		Conclusions
		References
	27: Genetics and Epigenetics of FASD
		Genetic Component to FASD
		Genetic Pathways Implicated in FASD
		Epigenetic Modifications that Occur as a Result of Alcohol Exposure in Humans and Animals
		Long-Term Effects of Prenatal Alcohol Exposure
		References
	28: Genetic, Epigenetic, and Environmental Influences on Fetal Alcohol Spectrum Disorder: Implications for Diagnosis, Research and Clinical Practice
		Introduction
		FASD as a Common Neurodevelopmental Disorder: Prevalence and Diagnosis
		Risk and Protective Factors for FASD: What Is the Evidence?
			Maternal and Environmental Factors
				Paternal Factors
		Genetics of FASD
			Genes and Cell Signaling Pathways Involved in FASD
				SHH Mutations and Signaling Pathway Impairments in FASD
				WNT Mutations and Signaling Pathway Impairments in FASD
				FGF Signaling Pathway
				BMP Signaling Pathway
				Retinoic Acid Deficiency and Signaling Pathway Impairments in FASD
			Susceptibility and Resilience Genes and Factors in FASD
			Co-Morbidities with Other Developmental Genetic Disorders
		Epigenetics of FASD
			DNA Methylation
			Chromatin Modifications
			Non-coding RNA
			Considerations for Epigenetic Research on FASD
		Transcriptomic and Proteomic Alterations of FASD
			Transcriptomic Alterations
			Proteomic Alterations
		Applications to Clinical Setting and Conclusions
		References
	29: Fetal Alcohol Spectrum Disorder: Interventions
		Introduction
		Targeted Interventions
			Self-Regulation and Behaviour
			Executive Functioning Abilities
			Academics
			Activities of Daily Living
		Integrated Interventions
			Boost Parental Capacity
			Nurture Parent-Child Relationships
			Increase Home Stability
			Promote Mental Health and Well-being
			Support Healthy Families
			Plan for Activities of Daily Living (ADL) during Transitional Years
		Adopting an Evidence-Based Intervention Framework
			Investing in Relationships
			Adopting a Strength-Based Perspective
			Creating Opportunities for Expectation and Engagement
			Recognizing FASD Is a Lifelong Disability
			Leveraging Existing Community Capacities
		Conclusions
		References
Part IV: Cerebral Palsy
	30: Cerebral Palsy: Clinical Vignettes
		Introduction
		Case #1
		Commentary-Case #1
		Case #2
		Commentary-Case #2
		Case #3
		Commentary-Case #3
		Case #4
		Commentary-Case #4
		Case #5
		Commentary-Case #5
		Conclusion
		References
	31: Cerebral Palsy: Epidemiology
		Introduction
		Definitions
		Prevalence
			High-Income Countries
			Low- and Middle-Income Countries
		Motor Type and Topography
		Classification Systems and Severity
		Risk Factors for CP
			Pre-Conception and Early Pregnancy
				Genetics
				Maternal Age
				Assisted Reproductive Technology
				Congenital Anomalies
				Multiple Birth
			Pregnancy
				Congenital Infections
			Perinatal
				Hypoxic Ischaemic Encephalopathy
				Low Gestational Age
		Post-Neonatally Acquired CP
		An Examination of Microcephaly in CP: Including Genetic and Environmental Influences
			Definition of Congenital Microcephaly
			The Case Control Study of Cerebral Palsy and Perinatal Death (CCCP)
			Percentage and Prevalence of Congenital Microcephaly in Children with CP in the CCCP
			Clinical Outcomes of Children with CP and Congenital Microcephaly
			Genetic and Environmental Pathways to CP That Include Congenital Microcephaly
				Genetic Pathways to CP Including Microcephaly: Known Genetic and Chromosomal Syndromes
				Genetic Pathways to CP Including Microcephaly: With Additional Congenital Anomalies
				Environmental Pathways to CP Including Microcephaly: Congenital Infections
				Prevention
				Pathways to CP Including Microcephaly That Remain Unclear
			The Special Case of Postnatally Developing Microcephaly in CP
		Conclusion
		References
	32: Diagnosis of Cerebral Palsy
		Introduction
		Perspectives
		Definition
		Classic Cerebral Palsy “Syndromes”
			Spastic Hemiplegia/Unilateral Spastic Cerebral Palsy
			Spastic Diplegia/Bilateral Spastic Cerebral Palsy (Predominantly Affecting Lower Limbs)
			Spastic Quadriplegia/Bilateral Spastic Cerebral Palsy (Affecting All Limbs)
			Dyskinetic (Extrapyramidal) Cerebral Palsy
			Mixed Cerebral Palsy
			Hypotonic Cerebral Palsy
			Ataxic Cerebral Palsy
			Developmental Coordination Disorder (DCD)
		Diagnostic Evaluation
			Etiologic Evaluation
			Individualized Evaluation
				Motor Abnormalities and Their Distribution
				Functional Classification
				Co-Existing Conditions
		Early Diagnosis
			Clinical Risk Factors
			Motor Dysfunction in Infancy
			Neuroimaging
			Severity, Type, and Topography Indicators
			Early Intervention
		Conclusion
		References
	33: Neuroradiology of Cerebral Palsy
		Introduction
		Available Imaging Techniques
			Head Ultrasound (HUS)
			Head Computed Tomography (CT)
			Brain Magnetic Resonance Imaging (MRI)
		Typical Neuroimaging Pattern of Some Perinatal Causes of CP
			Neonatal Encephalopathy
			Intraventricular Hemorrhage (IVH) and Periventricular Hemorrhagic Infarction (PVHI)
			Periventricular White Matter Injury (PWMI) or Periventricular Leukomalacia (PVL)
			Stroke
				Acute Perinatal Arterial Ischemic Stroke (PAIS)
				Presumed Perinatal Arterial Ischemic Stroke (PPAIS)
			Cerebral Venous Sinus Thrombosis (CVST)
			Central Nervous System Infections
				Bacterial Meningitis
				Herpes Simplex Virus (HSV)
			Kernicterus
		Typical Neuroimaging Pattern of Some Prenatal Causes of CP
			Congenital Brain Malformations
			Intrauterine Infections
				Congenital CMV (cCMV)
				Congenital Toxoplasmosis
		Typical Neuroimaging Pattern of Some Postnatal Causes of CP
			Non-Accidental Head Injuries (NAHI)
		End-of-Chapter Summary/Bullet Points
		References
	34: Neuropathology of Cerebral Palsy
		Introduction
			Aetiology and Pathogenesis
			Semantics
		Traditional and Modern Neuropathological Examination
		Neuropathological Changes in Brain Tissue in Cerebral Palsy
		Cerebral Dysgeneses or Malformations Associated with Cerebral Palsy
			Tuberous Sclerosis Complex (TSC), Hemimegalencephaly (HME) and Focal Cortical Dysplasia Type II (FCD II): Disorders of the mTOR Signalling Pathway
			Holoprosencephaly (HPE)
			Septo-optic-pituitary Dysplasia (du Morsier syndrome)
			Schizencephaly
			Polymicrogyria (PMG)
			Lissencephaly Types I and II
			Periventricular Nodular Heterotopia, Subcortical Laminar (‘band’) Heterotopia and Scattered Deep White Matter Heterotopia
		Cerebral Ischaemia and Infarcts in the Foetal and Perinatal Periods, Including Porencephaly
			Ulegyria
			Porencephaly
			Brainstem Watershed Infarcts
		Periventricular Leukomalacia, White Matter Gliosis, and the Roles of Iron and Zinc
			Historical Perspective and Descriptive Morphology
			Impediment of Oligodendrocytic Lineage in PVL
			Astrocytic Role
			Iron
			Zinc
			Grey Matter Lesions in PVL
			Basal Ganglia
			Cerebellum
		Congenital Infections
		Inborn Metabolic Encephalopathies
		Ventriculomegaly and Hydrocephalus
		Microcephaly
		References
	35: Genetics and Genomics of Cerebral Palsy
		Introduction
		Twin and Other Family Studies
		Candidate Gene Association Studies
		Studies of Chromosomal Abnormalities and Genomic Copy Number Variants
		Studies of Single Nucleotide Variants and Indels
		Epigenetic Studies
		The Genetics and Genomics of Cerebral Palsy
		References
	36: Pre-Clinical Models of Cerebral Palsy
		Introduction
			Cerebral Palsy Definition and Phenotypes
			Considerations of Animal Models
			Ideal Animal Model
		Pre-Clinical Animal Models
			Murid Rodents
			Placental Insufficiency
			Guinea Pig
			Rabbit
			Cat
			Pig
			Sheep
			Non-Human Primates
		Conclusion
		References
	37: Therapeutic Approaches for the Treatment of Cerebral Palsy and Developmental Disability
		Section I: Prevention
			Introduction
				Non-Preventable Risk Factors/Pregnancy Planning
				Education, Social Programs, and Consistent Healthcare Access
				Mechanisms of Fetal Brain Injury
				Prevention of Premature Birth
				Prevention of Infection
				Neuroprotection
					Magnesium Sulfate (MgSO4)
					Corticosteroids
					Other: Vitamin K, Phenobarbital
				Conclusions and Future Directions
		Section II: Therapeutic Hypothermia
		Section III: Rehabilitation in Cerebral Palsy
		CP Diagnosis
		Therapeutic Interventions
		Tone Management
		Orthotics and Mobility Devices
		Future Directions
		Section IV: Transcranial Magnetic Stimulation (TMS)
		Section V: Regenerative Approaches to Treating Cerebral Palsy
			Introduction
			Where to Target Stem Cell Therapies
			What We Know About Stem Cell Therapies
			Sources of Stem Cells
			Types of Multipotent Stem Cells for Cerebral Palsy
				Mesenchymal Stromal Cells and Hematopoietic Stem Cells
				Neural Precursor Cells
		Conclusions
		References
Part V: Co-Morbidities in Neurodevelopmental Disorders
	38: Sleep Disorders
		Introduction to Sleep Problems in Children with NDD
		What Is Sleep?
		Regulation of Sleep
		How Sleep Physiology Differs in Children with NDD Compared to TD Children
		What Are Sleep Disorders
		Etiology of Sleep Disorders in Children with NDD
		How to Evaluate Sleep Disorders and Considerations for Children with NDD
			Screening Assessment
			Subjective Assessment
			Objective Assessment
		How to Treat Sleep Disorders in Children with NDD
		Psychoeducation
		Healthy Sleep Practices
		Specific Behavioral Sleep Interventions
		Medication
		Transdiagnostic Approach to Treatment
		References
	39: Optimizing Therapy of Seizures in Children and Adolescents with Developmental Disabilities
		Introduction: Epilepsy and Developmental Disability
		Specific Developmental Disabilities
			Cerebral Palsy (CP)
				Prevalence and Pathophysiology of Comorbid Epilepsy
				Risk Factors for Development of Epilepsy in Cerebral Palsy
				Types of Epilepsy in Cerebral Palsy
				Natural History of Epilepsy Associated with Cerebral Palsy
				Management of Epilepsy in Cerebral Palsy
			Autism Spectrum Disorders
				Prevalence and Pathophysiology of Comorbid Epilepsy
				Risk Factors for Development of Epilepsy in ASD
				Types of Epilepsy in ASD
				Natural History of Epilepsy Associated with ASD
				Management of Epilepsy in ASD
			Cortical Malformations
				Prevalence and Pathophysiology of Comorbid Epilepsy
				Risk Factors for Development of Epilepsy with Cortical Malformations
				Types of Epilepsy Associated with Cortical Malformations
				Natural History of Epilepsy Associated with Cortical Malformations
				Management of Epilepsy Associated with Cortical Malformations
			Fetal Alcohol Syndrome
				Prevalence and Pathophysiology of Comorbid Epilepsy
				Risk Factors for the Development of Epilepsy
				Types of Epilepsy in Fetal Alcohol Syndrome
				Natural History of Epilepsy Associated with Fetal Alcohol Syndrome
				Management of Epilepsy in Fetal Alcohol Syndrome
		Investigation of Seizures in Children with Neurodevelopmental Disabilities
		Treatment of Seizures in Children with Neurodevelopmental Disabilities
		Summary Points
		Clinical Vignettes
		References
	40: Behavioral and Mental Health Disorders (Including Attentional Disorders)
		Introduction and Overview
		Adverse Childhood Experiences
		Behavioral and Mental Health Disorders in Children with Neurodevelopmental Disorders
		Autism Spectrum Disorders
			Persistent Deficits in Social Communication and Social Interaction Across Multiple Contexts
				Speech and Language
				Social Interaction
			Restricted, Repetitive Patterns of Behavior, Interests, or Activities
				Repetitive behaviors
				Unusual Sensory Reactions
				Tendency to Overreaction
				Psychiatric Comorbidities
				Anxiety
				Tics and Tourette’s
				ADHD
				Medical Conditions Expressing as Behavior Disorders
				Disparities in Diagnosis and Treatment of ASD
		Section Bullets
		Cerebral Palsy
			Conclusion
		Fetal Alcohol Spectrum Disorders FAS (D)
			Pathology and Pathophysiology
			Clinical Characteristics and Diagnosis
			Behavioral and Mental Health Concerns
			Social Context
			Behavioral and Mental Health
			Educational Concerns
			Transition to Adulthood
		Attention Deficit Hyperactivity Disorder (ADHD)
			Introduction
		The Evolution of Attention Deficit/Hyperactivity Disorder
		Overview of Neurodevelopmental Disorders
		Diagnostic Criteria for ADHD
		ADHD diagnostic criteria
		Co-occurring and Comorbid Conditions
		Assessment
		Trends in Treatment
		Summary
		Summary Bullets
		Chapter Discussion
		References
	41: Role of Gender and Neurodevelopmental Disabilities
		Introduction
		Neurodevelopmental Disabilities and Males
			Attention-Deficit/Hyperactivity Disorder (ADHD)
			Autism Spectrum Disorder (ASD)
			Intellectual Disability (Intellectual Developmental Disorder)
			Specific Learning Disorder
			Communication Disorders
			Tourette’s Disorder
			Cerebral Palsy
			Schizophrenia
		Neurodevelopmental Disabilities and Females
			Myelomeningocele
			Mental Health Disorders
				Eating Disorders
				Depressive Disorders
				Anxiety Disorders
			Other Conditions/Disorders
		In Utero Milieu: Protection Versus Toxicity
			Placental Milieu
			Epigenetic Role of O-Linked N-Acetylglucosamine Transferase (OGT)
		Conclusions
		References
	42: A Non-Categorical Approach to Childhood Neurodisability: Concepts, Evidence, and Implications for Clinical Practice, Organization of Services, Teaching, and Research
		Introduction
		Background Concepts
		The Non-categorical Approach: Overview
		The Case for a Non-categorical Approach in Childhood Neurodisability
		The Non-categorical Approach: State of the Evidence
		Implications of These Ideas
		Concluding Comments
		References
	43: Pain and Symptom Management in Neurodevelopmental Disorders: Sensory and Nociceptive Function/Pain and Symptom Management
		Background and Significance
		Approaches and Challenges to Pain Assessment in IDD
			Sensory Measurement
			Observational Measurement
			Proxy Report
			Biomarkers
			Neuroimaging
		Current Assessment and Treatment Approaches
			Assessment
			Treatment
		Knowledge Transfer
			Secondary Caregivers—A Literature Gap, Current Work, and Continued Future Directions
		Continuing Issues and Hope for the Future
		Summary
		References
	44: Pharmacology, Psychopharmacology, and Adverse Drug Reactions
		Introduction
		Psychopharmacology as a Subset of Basic Pharmacology
		Pharmacogenomics
		Pharmacogenetics (See Appendix 1)
		Pharmacokinetics
			Bullets
		Pharmacodynamics
			Bullets
		Precision Medicine
			Bullets
		Classifying Psychiatric Disorders
			Bullets
		Summary, Synthesis, and Conclusions
		Appendix 1. Current Applications of Pharmacogenetics to the Psychiatry Treatment
			Limitations
		Appendix 2. What New Treatment Ideas Are on the Horizon?
		References
	45: Developmental Origins, Differential Susceptibility, and Resilience in Neurodevelopmental Disorders
		Introduction
		The Developmental Origins of Health and Disease
			Critical Periods of Sensitivity
			Sensitive Periods of Brain Development
		Early Life Environmental Factors That Influence Brain Development and Susceptibility to Neurodevelopmental Disorders
			Prenatal Environments
				Prenatal Nutritional Environment
				Maternal Metabolic State and Hypertensive Disorders in Pregnancy
				Maternal Mood, Anxiety and Adverse Life Events
					Prenatal Depression
					Prenatal Worries and Anxiety
					Adverse Life Events
					Prenatal Stress and Genetic Susceptibility
					Mechanism
					Sex-Specific Responses
				Summary
			Postnatal Modifiers of Prenatal Programming
				Toxicants, Nutrition, and the Microbiome
				Sleep Hygiene
				Mind and Body
				Rearing Environment
		Modeling the Joint Effect of Genetic Susceptibility and Environmental Exposures in Developmental Programming
			The Three Types of Gene-by-Environment Interactions Models
			Definition of a G×E Model
			Components of the G×E Model
				Environment
				Genetics
			How to Test for the Type of Interaction?
			Modeling with Examples
		Conclusions
		References
Part VI: Neurodevelopmental Disorders in the Context of Families
	46: Children with Neurodevelopmental Disabilities and the Right to Health
		An Introduction to Human Rights and Rights-Based Approaches in Childhood Disabilities
		Human Rights Application in Signatory Countries
		The Right to Health and Its Intersections with Health Frameworks
		The Right to Health and Childhood Disability
		Rights-Based Approaches in Childhood Disabilities: What Is the Research Evidence?
		Applying Rights-Based Approaches to Health Care and Research
		Conclusions
		References
	47: Patient Navigation: Core Concepts and Relevance to the Field of Pediatric Neurodisability
		Introduction
		Patient Navigation: Origins and Core Concepts
		Patient Navigation and Children with NDD/D
			Insights from Quality Improvement
			Insights from Empirical Evidence
			Navigation and its Alternatives
		Moving the Field Ahead: Challenges and Opportunities
		Concluding Thoughts
		References
	48: Evaluating the Economic Impact of Neurodevelopmental Disability Intervention on the Family and Community
		Introduction
		Considering the Perspective and Time Horizon for an Evaluation
			Evaluation Perspective
			Time Horizon and Discounting
		Measurement of NDD Costs
			Direct Costs
			Indirect Costs
		Measurement of NDD Effectiveness
		Economic Evaluation of Interventions for Children with NDD
			Cost of Illness (COI)
		Types of Economic Evaluations
			Cost Minimization (CMA)
			Cost-Effectiveness Analysis (CEA)
				General Health Profile Measures
				ASD, CP, and FASD-Specific Measures
			Cost-Utility Analysis (CUA)
				Preference-Based HRQoL Measures
			Cost-Benefit Analysis (CBA)
		Measurement of Family Effects and Caregiver Effects
		Challenges for the Economic Evaluation of NDD
			Important Considerations when Choosing Outcome Measures
			Important Considerations when Incorporating Caregivers and Family Effects
			Important Considerations when Estimating Costs
		Conclusions
		References
Part VII: Resources
	49: Using Large-Scale Population-Based Data
		Introduction
		Large-Scale Population-Based Survey Data
		Large-Scale Population-Based Administrative Data
		Record Linkage
		Research Examples
		Criteria to Assess a Secondary Data Source for Data Analysis in Neurodevelopmental Pediatrics
		Summary
		References
	50: Tools for Knowledge Dissemination and Translation to Help Your Journey from Research to Impact
		Introduction
		Section 1: The Co-Produced Pathway to Impact (CPPI)—You Need to Know How to Get There from Here
		Section 2: Research to Impact Canvas—You Need to Know How to Plan to Get There from Here
		Section 3: Stakeholder Engagement—You Need to Know Why You Are Trying to Get There from Here and Where “There” Is
		Section 4: Dissemination—Necessary But Not Sufficient to Get There from Here
		Section 5: International Perspectives—Others Are Also Trying to Get There
		Conclusion
		References
Index