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Book Details
Abstract
This book focuses on the emerging and expanding areas of research on ASD and their potential to lead to better diagnosis and more effective therapies. These areas include innovative and integrative approaches to genetic/genomic analyses and investigations of epigenetic contributions, including the role of noncoding RNAs, DNA methylation, alternative splicing, RNA editing, and faulty translation in gene regulation and expression, metabolic and immune dysfunction, co-morbidities, as well as hormonal and gene-environment interactions that may increase risk for ASD.Within each chapter, experts review cutting-edge research as well as provide their perspective on the future of research in their respective areas, including the challenges involved and the types of studies or advances that are necessary to move the field forward to achieve predicted translational goals.Contributors: Argel Aguilar-Valles, Evdokia Anagnostou, Emma Ashwin, Bonnie Auyeung, Kelly M Bakulski, Simon Baron-Cohen, Margaret L Bauman, Donna Betts, Chad A Bousman, Daniel B Campbell, Manuel F Casanova, Bhismadev Chakrabarti, Gursharan Chana, Abha Chauhan, Ved Chauhan, Jessica DeWitt, Keith W Dunaway, Alal Eran, Ian P Everall, M Daniele Fallin, Richard E Frye, Piers Gillett, Matthew Ginsberg, Christos G Gkogkas, Rhonda J Greenhaw, Simon G Gregory, Elena L Grigorenko, Feng Gu, Rebecca Harmer, Martha Herbert, Valerie W Hu, Karen L Jones, Petra Kern, Arkady Khoutorsky, Rebecca Knickmeyer, Isaac S Kohane, Louis M Kunkel, Janine M LaSalle, Michael V Lombardo, Deepali Mankad, Marvin Natowicz, Laura Nicholls, Christos Pantelis, Natalia Rakhlin, Radhika Ramadas, Daniel A Rossignol, Tewarit Sarachana, Stephen W Scherer, Gabriela Schmulevich, Ayten Shah, Frank R Sharp, Alison B Singer, Efstratios Skafidas, Estate M Sokhadze, Nahum Sonenberg, Boryana Stamova, Zohreh Talebizadeh, Renee Testa, Judy Van de Water, Irina Voineagu, Daniel Williams, Ryan K C Yuen, Daniela Zantomio.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Contents | vii | ||
| Dedication | v | ||
| Preface | xi | ||
| About the Editor | xv | ||
| List of Contributors | xvii | ||
| Dissecting the Genetic Architecture of ASD | 1 | ||
| Chapter 1 Phenotype Definition: A Cornerstone of Autism Research, Diagnosis and Therapy | 3 | ||
| Introduction | 4 | ||
| Heterogeneity: Categorical and Dimensional Approaches to Stratification of ASD | 5 | ||
| Incorporation of ASD Phenotypes into Transcriptome Analyses | 7 | ||
| Subtype-dependent Class Prediction Analyses for Biomarker Identification | 9 | ||
| Value of ADI-R-derived Phenotypic Subgroups in Genetic Analyses | 12 | ||
| Value of Phenotype-Definition for Targeted Therapies and Pharmacogenomics | 13 | ||
| Future Directions | 15 | ||
| Executive Summary | 16 | ||
| Acknowledgements | 17 | ||
| References | 17 | ||
| Chapter 2 From Molecular Pathways to ASD Therapy: Insights from Syndromic Forms of Autism | 23 | ||
| Introduction | 24 | ||
| Genetics of Idiopathic ASD | 26 | ||
| Common genetic variation | 26 | ||
| Rare genetic variation | 27 | ||
| Syndromic ASD | 28 | ||
| Rett syndrome | 29 | ||
| Fragile X syndrome | 30 | ||
| Tuberous sclerosis | 32 | ||
| Emerging Pharmacological Therapies for Syndromic ASD | 34 | ||
| Evidence for Convergent Pathways between Syndromic and Idiopathic ASD | 34 | ||
| Future Directions | 37 | ||
| Executive Summary | 38 | ||
| References | 38 | ||
| Chapter 3 Language Impairment in Autism Spectrum Disorders | 47 | ||
| Introduction | 47 | ||
| Language Impairments in ASD | 50 | ||
| Sources of phenotypic heterogeneity | 50 | ||
| Types of language deficits in ASD | 52 | ||
| Language skills and the diagnosis of ASD | 56 | ||
| Family Studies of ASD and LD Overlap | 56 | ||
| Molecular Genetic Studies of ASD/LD Overlap | 57 | ||
| Conclusions | 58 | ||
| Future Directions | 60 | ||
| Executive Summary | 60 | ||
| Acknowledgements | 61 | ||
| References | 61 | ||
| Chapter 4 Whole Genome Sequencing in Autism: Clinical Translation | 69 | ||
| Introduction | 70 | ||
| Understanding of ASD Genetics from Pre- and Post-high-throughput Sequencing Eras | 71 | ||
| Genetic architecture of ASD — Knowledge before the advent of high-throughput sequencing | 71 | ||
| Genetic discoveries from high-throughput sequencing | 74 | ||
| Strategies of Analyzing the Genetic Variants Identified by WGS | 76 | ||
| Genetic variant discovery | 78 | ||
| De Novo SNVs and indels | 79 | ||
| Manual assessment of potential de novo exonic variants | 79 | ||
| CNV detection by WGS | 80 | ||
| Rare variant characterization | 81 | ||
| Medical classification | 82 | ||
| Implications of ASD Whole Genome Sequencing on Diagnosis and Treatment | 83 | ||
| Revealing clinical and genetic heterogeneity of ASD | 84 | ||
| Facilitating decision-making on medical management | 84 | ||
| Providing potential pharmacological clues | 85 | ||
| Increasing diagnostic yield with improved genomic coverage | 85 | ||
| Future Directions of Autism Clinical Genetic Research using Whole Genome Sequencing | 86 | ||
| Resolving incomplete penetrance and variable expressivity of variants | 87 | ||
| Improving the quality of CNV calling from whole genome sequencing | 87 | ||
| Analyzing non-coding regions in the genome | 88 | ||
| Conclusion | 89 | ||
| Executive Summary | 89 | ||
| Acknowledgements | 90 | ||
| References | 91 | ||
| Chapter 5 The Impact of Integrative Unconventional Data Analysis Approaches on Advancing Autism Genetics Research | 99 | ||
| Introduction | 100 | ||
| Whole Genome Studies | 100 | ||
| Gender Bias in Autism | 104 | ||
| Phenotypic Stratification | 107 | ||
| Network Analysis | 109 | ||
| Interactome Networks | 110 | ||
| Future Directions | 111 | ||
| Executive Summary | 112 | ||
| References | 113 | ||
| Chapter 6 Construction of a Genetic Classifier for ASD Using Gene Pathway Analysis | 119 | ||
| Introduction | 120 | ||
| Clinical Diagnosis of ASD | 121 | ||
| Genetic Studies in ASD | 125 | ||
| Monogenic disorders with increased incidence of ASD | 125 | ||
| Copy number variants (CNVs) in ASD | 126 | ||
| Single nucleotide polymorphisms (SNPs) in ASD | 127 | ||
| Development of a Genetic Classifier for ASD using Gene Pathway Analysis | 127 | ||
| SNP quality control | 132 | ||
| Determining Ethnicity/Ancestry and Controlling for Population Stratification | 133 | ||
| Development of Genetic Classifiers for Other Psychiatric Disorders | 134 | ||
| Future Directions | 135 | ||
| Executive Summary | 136 | ||
| Acknowledgements | 137 | ||
| References | 137 | ||
| Gene Dysregulation in ASD: From Transcription to Translation | 145 | ||
| Chapter 7 Genome-Wide Expression Studies of Blood and Lymphoblastoid Cell Lines in Autism Spectrum Disorders | 147 | ||
| Introduction | 148 | ||
| mRNA Expression Studies of LCL in ASD | 150 | ||
| microRNA ( miRNA) Expression Studies of LCL in ASD | 152 | ||
| RNA Expression Studies in Relation to Genotype | 153 | ||
| RNA Expression Studies of Blood in ASD | 154 | ||
| Pathways Associated with ASD | 160 | ||
| Examining Dysregulated Pathways in Individual ASD Subjects | 161 | ||
| Importance of Pathway Studies for ASD | 162 | ||
| Future Directions | 164 | ||
| Executive Summary | 165 | ||
| References | 166 | ||
| Chapter 8 Searching in the “Dark”: Non-coding RNA as a New Avenue of Autism Research | 175 | ||
| Introduction | 176 | ||
| The Genomic “ Dark Matter” | 178 | ||
| Non-coding RNAs and ASD | 179 | ||
| miRNAs and ASD | 179 | ||
| snoRNAs and ASD | 188 | ||
| Biological functions associated with ncRNAs reported in ASD | 190 | ||
| Future Directions in ASD Biomarker Research | 192 | ||
| Executive Summary | 195 | ||
| Acknowledgements | 196 | ||
| References | 196 | ||
| Chapter 9 Targeting Noncoding RNA for Treatment of Autism Spectrum Disorders | 203 | ||
| Evidence that lncRNAs Contribute to ASD | 203 | ||
| What is a ncRNA? | 207 | ||
| Small ncRNA | 208 | ||
| Long ncRNA (lncRNA) | 209 | ||
| Therapeutic Targeting of ncRNA — A New Type of Pharmacology | 210 | ||
| Cancer | 210 | ||
| Neurodegenerative Disorders | 212 | ||
| Ataxias | 212 | ||
| Alzheimer’s disease | 213 | ||
| Neurodevelopmental Disorders | 214 | ||
| Fragile X syndrome | 214 | ||
| Down’s syndrome | 214 | ||
| NcRNA in Clinical Trials | 215 | ||
| Future Directions and Conclusions | 217 | ||
| Executive Summary | 218 | ||
| References | 218 | ||
| Chapter 10 A-to-I RNA Editing in Autism Spectrum Disorder | 229 | ||
| Introduction | 230 | ||
| A-to-I RNA Editing Enables Fine-tuned Response to Environmental Cues | 231 | ||
| A-to-I RNA Editing Modulates Complex Behavior in Model Organisms | 233 | ||
| The Genomics Technology Revolution is Enabling Rapid Discoveries of A-to-I RNA Editing in Humans | 234 | ||
| A-to-I RNA Editing in Postmortem Brains of Children with ASD | 235 | ||
| Future Directions | 238 | ||
| Executive Summary | 239 | ||
| Acknowledgements | 240 | ||
| References | 240 | ||
| Chapter 11 Translational Control of Autism and Fragile-X Syndrome | 249 | ||
| Introduction | 250 | ||
| mRNA translation | 250 | ||
| Translational control | 251 | ||
| Autism Spectrum Disorders (ASD) | 253 | ||
| Fragile-X Syndrome (FXS) | 255 | ||
| Dysregulated translational control in ASD | 257 | ||
| Dysregulated translational control in FXS | 260 | ||
| Future Perspectives | 263 | ||
| Translation is a “druggable” pathway | 263 | ||
| Clinical trials in FXS and ASD | 264 | ||
| Executive Summary | 267 | ||
| References | 268 | ||
| Epigenetic, Environmental, and Physiological Contributions to ASD | 277 | ||
| Chapter 12 Epigenetics in Autism | 279 | ||
| Introduction | 279 | ||
| Fundamentals of Epigenetics | 280 | ||
| Epigenetics in Disease | 283 | ||
| Syndromic Autism | 285 | ||
| Fragile X syndrome | 285 | ||
| Rett syndrome | 286 | ||
| Angelman syndrome | 287 | ||
| Environmental Epigenetics | 288 | ||
| Epigenetic Dysregulation in Non-Syndromic Autism | 289 | ||
| Potential Sources of Epigenetic Dysregulation | 291 | ||
| Future Directions | 292 | ||
| Conclusions | 294 | ||
| Executive Summary | 295 | ||
| References | 295 | ||
| Chapter 13 The Epigenetics of Autism — Running Beyond the Bases | 303 | ||
| Introduction | 303 | ||
| DNA Methylation | 304 | ||
| Regulation by DNA Methylation | 308 | ||
| Epigenetics and Autism | 309 | ||
| MECP2 | 309 | ||
| FRAX | 310 | ||
| Angelman/Prader-Willi syndromes | 310 | ||
| 15q11-13 | 311 | ||
| Chromosome 7 | 312 | ||
| Methylation pathways | 312 | ||
| Candidate Genes | 313 | ||
| OXTR | 313 | ||
| SHANK3 | 314 | ||
| RELN | 314 | ||
| PRRT1 and ZFP57 | 315 | ||
| Influences of the Environment on the Epigenome | 315 | ||
| Assisted Reproduction | 316 | ||
| Technologies for Profiling of DNA Methylation | 317 | ||
| Histones and Chromatin Modifications | 319 | ||
| Histones and Autism | 321 | ||
| Future Directions | 321 | ||
| Executive Summary | 322 | ||
| Acknowledgements | 323 | ||
| References | 323 | ||
| Chapter 14 Genes and Environment in Autism Spectrum Disorders: An Integrated Perspective | 335 | ||
| Etiologic Models for ASD — Genes, Environment, or Both? | 335 | ||
| Heritability evidence | 337 | ||
| Historical perspective on genetic and environmental etiologic work in ASD | 337 | ||
| Genetic Risk Factors for ASD | 338 | ||
| Inherited genetics in ASD | 339 | ||
| De novo genetic change in ASD | 340 | ||
| Genetics summary | 340 | ||
| Environmental Risk Factors for ASD | 341 | ||
| Windows of susceptibility | 341 | ||
| Parental characteristics | 342 | ||
| Toxicants | 343 | ||
| Combined Genetic and Environmental Risk Paradigm | 346 | ||
| The potential applications of gene-environment interaction studies | 346 | ||
| GxE mechanisms | 348 | ||
| Current GxE autism epidemiology studies | 352 | ||
| Challenges and Suggestions for an Integrated Approach | 353 | ||
| Genetic measures | 353 | ||
| Exposure assessment | 354 | ||
| Phenotype assessment | 356 | ||
| Analysis tools | 356 | ||
| Study designs and available samples | 357 | ||
| Summary and Future Directions | 358 | ||
| Executive Summary | 359 | ||
| References | 360 | ||
| Chapter 15 The Potential Brain Drain from Environmental Exposures on the Methylome and Genome Across Generations | 375 | ||
| Why Consider a Potential Chemical “ Brain Drain” of Generationally Cumulative Environmental Exposures in Autism Risk? | 376 | ||
| The Complex Etiology of Autism Spectrum Disorders | 376 | ||
| DNA Methylation at the Interface of Genomic Interactions with the Environment | 378 | ||
| The Neuronal Methylome and Its Importance in Autism | 379 | ||
| How Do Environmental Toxins Affect Metabolic Pathways Regulating DNA Methylation? | 382 | ||
| Evidence for Environmental Exposures Affecting Brain Methylation | 384 | ||
| Evidence for Transgenerational Effects of Environmental Exposures | 389 | ||
| Evidence for Environmental Exposures and Transgenerational Effects in ASD | 392 | ||
| Future Directions | 393 | ||
| Executive Summary | 395 | ||
| References | 396 | ||
| Chapter 16 Oxidative Stress and Mitochondrial Dysfunction in ASDs | 407 | ||
| Introduction | 408 | ||
| Oxidative Stress in Autism | 410 | ||
| Increased markers of oxidative damage in autism | 410 | ||
| Decreased antioxidant defense in autism | 411 | ||
| Mitochondrial Dysfunction in Autism | 412 | ||
| Defects in energy metabolism in autism | 413 | ||
| Defects in activities and protein expression of mitochondrial ETC complexes in autism | 414 | ||
| Defects in mtDNA in autism | 415 | ||
| Defects in maintaining calcium homeostasis in autism | 417 | ||
| Future Perspectives | 417 | ||
| Executive Summary | 418 | ||
| References | 419 | ||
| Chapter 17 Maternal Autoantibodies in Autism Spectrum Disorder | 429 | ||
| Introduction | 429 | ||
| Immune Review | 430 | ||
| Immune system overview | 430 | ||
| Maternal immunity and the gestational environment | 431 | ||
| Maternal Autoantibodies in Autism | 433 | ||
| Observational studies | 433 | ||
| Animal models | 436 | ||
| Maternal antibodies and genetic susceptibility | 438 | ||
| Future Directions | 439 | ||
| Conclusions | 440 | ||
| Executive Summary | 444 | ||
| References | 444 | ||
| Chapter 18 Why is Autism More Common in Males? | 451 | ||
| The Male Bias in Autism | 452 | ||
| Are ASC an Extreme Expression of the Male Brain? | 453 | ||
| Sexual Dimorphism in the Human Brain | 454 | ||
| The Fetal Testosterone (fT) Theory | 456 | ||
| Fetal androgens affect the brain: Evidence from animal and human studies | 456 | ||
| Fetal androgens affect ASC traits: Evidence from amniotic fluid testosterone | 457 | ||
| Future Directions | 459 | ||
| Executive Summary | 461 | ||
| Acknowledgments | 461 | ||
| References | 461 | ||
| Moving Towards Personalized Treatment of ASD and Lifespan Issues | 471 | ||
| Chapter 19 Future Directions in Psychopharmacology of Autism Spectrum Disorder | 473 | ||
| Introduction | 474 | ||
| Stratification Based on Biomarkers | 475 | ||
| Medications Targeting Emerging Pathophysiology of ASD | 476 | ||
| Drugs altering the excitation to inhibition (E:I) balance | 476 | ||
| Immune Modulators | 479 | ||
| Medications that Target Neurocircuitry which May Modify Severity of Core Symptoms | 483 | ||
| Future Directions: Combining Pharmaco-therapeutics Targeting the Biology of ASD with Behavioral Interventions | 485 | ||
| Conclusion | 485 | ||
| Executive Summary | 486 | ||
| References | 486 | ||
| Chapter 20 Medical Co-Morbidities in Autism: Clues to Underlying Biological Mechanisms and/or Diagnostic Subtypes? | 497 | ||
| Introduction | 498 | ||
| Seizure | 499 | ||
| Gastrointestinal Disorders | 501 | ||
| Sleep Disorders | 503 | ||
| Metabolic Disorders | 505 | ||
| Mitochondrial disorders | 505 | ||
| Other potentially significant metabolic disorders | 507 | ||
| Discussion | 509 | ||
| Future Directions | 511 | ||
| Executive Summary | 511 | ||
| References | 512 | ||
| Chapter 21 Translational Implications of a Whole-Body Approach to Brain Health in Autism: How Transduction between Metabolism and Electrophysiology Points to Mechanisms for Neuroplasticity | 515 | ||
| Introduction | 516 | ||
| Beyond Hardwired: Autism Not Born but Made | 517 | ||
| What are These New Observations Telling Us About How Autism “Works”? | 520 | ||
| New Directions for Research and Treatment: Whole-Body Approach to Brain | 521 | ||
| How a Whole Body Approach Reframes the Role of the Brain in Autism | 522 | ||
| Multi-Scale Interacting Aspects of Brain Biology and Function | 523 | ||
| Problems in the body that have parallels in the brain | 523 | ||
| Brain: Transduction between Physical and Informational Levels | 524 | ||
| Brain as a Physical Organ: The Poorly Explored Relationships between Anatomy and Pathophysiology | 525 | ||
| Microscopic findings | 525 | ||
| Macroscopic findings | 528 | ||
| Brain as a System for Information Processing | 530 | ||
| “ Structural connectivity” through fiber tracts | 531 | ||
| Specific regions that “light up” during brain activity | 532 | ||
| Tissue-level contributors to brain activation measured by fMRI | 532 | ||
| Problems with blood perfusion of brain tissues | 533 | ||
| Electrical oscillations or “brain waves” | 534 | ||
| Temporal vs. spatial resolution of measurements and learning about autism as a PROCESS | 534 | ||
| Molecular and Cellular Underpinnings of Brain Information Processing | 535 | ||
| Underlying systems supporting brain function: Differences between cell types | 535 | ||
| Underlying systems supporting brain function: Gap junctions and voltage-gated calcium channels | 536 | ||
| Fast Tracking Progress in Autism Research: From Bottom-up to Middle-out and Multi-scale Approaches | 538 | ||
| A Further Problem: Heterogeneity — How Can There be So Many Routes to “Autism”? | 539 | ||
| Okay, So What “is” the “Autism” Anyway? | 540 | ||
| Autism as an Emergent Property of a System with Many Shifted “Settings” | 541 | ||
| From “what causes autism” to “how is autism caused” | 542 | ||
| From “how is autism caused” to “how does autism work”: Dynamical process approach | 542 | ||
| Autism as What Emerges from the Moment-to-Moment Impact on Electrophysiology of Depleted Function of Cells Supporting Brain Electrical Activity | 543 | ||
| Practical Implications for Conducting Research and Clinical Care? | 544 | ||
| Lifestyle interventions for the brain: Public health implications | 544 | ||
| What it Will Take to Implement a Public Health, Everyday Epigenetics Approach to Autism | 545 | ||
| Future Directions: Toward True Translational Research | 545 | ||
| Conclusion: Multi-Scale Dynamical Biology Gives Hope and Empowerment | 546 | ||
| Executive Summary | 547 | ||
| References | 548 | ||
| Chapter 22 Achieving Optimal Outcomes in Autism: Treating Potentially Reversible Conditions Associated with Autism Spectrum Disorder | 557 | ||
| Introduction | 558 | ||
| Specific Metabolic Disorders Amenable to Novel Treatments | 560 | ||
| Mitochondrial metabolism | 560 | ||
| Folate metabolism | 563 | ||
| Redox metabolism | 566 | ||
| Tetrahydrobiopterin metabolism | 567 | ||
| Common Molecular Mechanisms are Associated with Novel Treatments | 568 | ||
| Future Prospective | 570 | ||
| Executive Summary | 571 | ||
| References | 572 | ||
| Chapter 23 Transcranial Magnetic Stimulation: Application in Autism Treatment | 583 | ||
| Introduction | 584 | ||
| Inhibition Defects in Autism and the Potential Role of TMS | 587 | ||
| Electrophysiological Studies on Autism | 589 | ||
| Our Studies in Autism using rTMS | 592 | ||
| Conclusions | 597 | ||
| Future Directions | 598 | ||
| Executive Summary | 599 | ||
| References | 600 | ||
| Chapter 24 Music Therapy: Personalized Interventions for Individuals with Autism Spectrum Disorder | 607 | ||
| Introduction | 608 | ||
| Why Music Matters | 608 | ||
| Music Therapy Services for ASD | 609 | ||
| Professional health discipline | 609 | ||
| Music therapy practice | 610 | ||
| Therapeutic process | 610 | ||
| Music Therapy Intervention Studies | 611 | ||
| Building on the past: Anecdotal reports and narrative literature reviews | 611 | ||
| Learning from the data: Three systematic reviews | 612 | ||
| Moving forward: Emerging research and initiatives | 614 | ||
| Outlook on Future Research and Developments | 617 | ||
| Sample size and scientific rigor | 618 | ||
| Goal areas and aspects of interventions | 619 | ||
| Context of intervention and collaborations | 619 | ||
| Research to practice | 620 | ||
| Conclusion | 621 | ||
| Executive Summary | 622 | ||
| Acknowledgements | 623 | ||
| References | 623 | ||
| Chapter 25 The Contributions of Art Therapy in Treatment, Assessment, and Research with People Who Have Autism Spectrum Disorders | 627 | ||
| Introduction | 628 | ||
| Art Therapy | 628 | ||
| Art Therapy and Autism | 628 | ||
| Art Therapy Treatment & Autism | 630 | ||
| Art Therapy School-Based Programs | 633 | ||
| Family Art Therapy and Autism | 634 | ||
| Art Therapy Assessment & Autism | 636 | ||
| The FSA: Case Examples | 638 | ||
| Future Directions: Art Therapy Research & Autism | 643 | ||
| Neuroscience, Art Therapy and Autism | 647 | ||
| Executive Summary | 648 | ||
| References | 648 | ||
| Appendix A: Martin’s (2009) characteristics of artwork by children with autism: Definitions of terms | 653 | ||
| Chapter 26 Shifting Paradigms: An Examination of Our Understanding of Adult Autism | 655 | ||
| Introduction | 656 | ||
| Conditions Impacting Adults on the Spectrum | 657 | ||
| Therapeutic and medicated childhoods | 657 | ||
| Bullying, abuse and isolation | 658 | ||
| Co-occurring conditions | 659 | ||
| Housing | 660 | ||
| Education | 661 | ||
| Transition-aged youth | 661 | ||
| New post-secondary academic options | 662 | ||
| Post-secondary training options | 664 | ||
| Employment | 664 | ||
| Supported employment | 666 | ||
| Work-based learning and job trials | 666 | ||
| Customized employment | 667 | ||
| Future Trends in Adult Autism | 668 | ||
| Translational research | 668 | ||
| Psychiatry | 669 | ||
| Embracing the social model of disability | 670 | ||
| Trauma-informed programming | 675 | ||
| Technology and social media and peer-to-peer support | 675 | ||
| Executive Summary | 677 | ||
| References | 678 | ||
| Index | 683 |