New Discoveries in the Behavioral Neuroscience of Attention-Deficit Hyperactivity Disorder

Preface
Contents
ADHD in Children and Adults: Diagnosis and Prognosis
1 Introduction
2 Diagnosis
3 ADHD in Preschool Children
4 ADHD in School-Aged Children
5 ADHD in Adolescents
6 ADHD in Adults
7 Conclusion
References
Current Pharmacological Treatments for ADHD
1 Introduction
2 Medications for ADHD and Their Mechanism of Action
2.1 Stimulant Medications
2.1.1 Methylphenidate
2.1.2 Amphetamine
2.2 Nonstimulants
2.2.1 Atomoxetine
2.2.2 Guanfacine and Clonidine
3 Pharmacokinetics of ADHD Medications
4 ADHD Medications and the Cognitive Neuroscience of ADHD
5 Efficacy and Tolerability: Comparison Between Medications
6 Effects of ADHD Medications on Other Outcomes and Comorbidities
7 Factors to Consider When Choosing Treatments
8 Conclusions
References
The Benefits and Limitations of Stimulants in Treating ADHD
1 Introduction
2 Stimulants Used to Treat ADHD
3 Political, Ethical, and Moral Issues Relating to the Use of Stimulants for the Treatment of ADHD
4 The Treatment of Subsyndromal ADHD and the Use of Stimulants as Cognitive Enhancers
5 Comparative Efficacy Between Stimulants and Non-pharmacological Treatments for ADHD
6 Comparative Efficacy, Effectiveness, and Safety of Pharmacological Treatments for ADHD
6.1 Children and Adolescents
6.2 Adults
6.3 Comparisons Between Different Stimulant Formulations
7 Clinical Implications of These Findings
8 Monitoring Treatment Response and the Potential Benefits of Integrating Measurement-Based Care Approaches into Clinical Prac...
9 Do Stimulants Work and Are They Safe Over the Long Term?
10 Considerations for Different Clinical Populations
11 Summary and Conclusions
References
New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development
1 Introduction
2 Current Status of Drugs to Treat ADHD
3 Non-clinical and Clinical Pharmacology of Approved Drugs to Treat ADHD
3.1 Lisdexamfetamine
3.2 Viloxazine
3.3 Prodrugs for Methylphenidate
3.4 Comment (Summary/Overview)
4 Update on the Progress of R&D in the Search for New Drugs to Treat ADHD
4.1 Centanafadine
4.2 Mazindol
4.3 Dasotraline
4.4 Vortioxetine
4.5 Droxidopa
4.6 Baicalin
4.7 Summary
5 Progress in the Pharmacological Management of ADHD
5.1 Efficacy in ADHD
5.2 Once-Daily Medication
5.3 Relapse on Withdrawal
5.4 Drug-Induced Side Effects
5.5 Abuse Liability
6 The Link Between ADHD and Binge-Eating Disorder
7 Concluding Remarks
References
Effects of Methylphenidate on the Dopamine Transporter and Beyond
1 Introduction
2 Methylphenidate and the Central Catecholamine Systems
2.1 Methylphenidate and the Catecholamine Transporters
2.2 Methylphenidate and Other Catecholamine Protein Targets
2.3 Summary: Methylphenidate and the Catecholamine Systems
3 Metabolomic Studies and Methylphenidate
3.1 Application of 1H-NMR-Based Metabolomics Provides New Insights Into the Mechanism of Action of Methylphenidate
3.2 Methylphenidate Increases Brain Tissue Amino-Acid Neurotransmitter Content
3.2.1 Methylphenidate Increases Brain Content of Large Neutral Amino Acids
3.3 Methylphenidate Alters Energy Metabolism and Membrane-Related Metabolites
3.4 Summary: Metabolomic Studies and Methylphenidate
4 Methylphenidate and Neuroplasticity
4.1 Methylphenidate and the Regulation of Genes and Proteins Mediating Neuroplasticity
4.2 Summary: Methylphenidate and Neuroplasticity
5 Conclusions
References
Comorbidity of Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorders: Current Status and Promising Directions
1 Introduction
2 Prevalence of Comorbidity
2.1 Role of Development
2.2 Sex Differences
3 Impact of Comorbidity on Adaptive Outcomes
3.1 Psychopathology
3.2 Adaptive Behavior
4 Causal Pathways
4.1 Functional Domains
4.2 Brain Correlates
4.3 Genetics
5 Future Directions
5.1 Design Characteristics
5.2 Sources of Heterogeneity
5.3 Treatment
6 Concluding Remarks
References
Adult Attention-Deficit Hyperactivity Disorder/Substance Use Disorder Dual Disorder Patients: A Dual Disorder Unit Point of Vi...
1 Neurobiological Mechanisms of Attention-Deficit Hyperactivity Disorder (ADHD) and Substance Use Disorders (SUDs)
1.1 Emotional Dysregulation and Core Symptomatology
1.2 Reward Craving and Relief Craving
2 Clinical Aspects of ADHD/SUD Patients Recruited in a Dual Disorder Unit
2.1 Four Dimensions of ADHD Patients
2.2 Two-Dimensional ADHD/SUDs
3 Pharmacotherapeutic Strategies for the Treatment of Attention-Deficit Hyperactivity (ADHD) Disorder with Comorbid Substance ...
3.1 From Intense to Occasional Use of Cocaine in Dual Disorder (Adult Attention-Deficit Hyperactivity Disorder/Cocaine Use Dis...
3.2 Exploring the Controversial Role of Caffeine in Adult ADHD Symptom Severity of US Army Soldiers
3.3 Influence of Substance Use Disorder on Retention in Treatment of A-ADHD Patients
4 Conclusions
References
Sleep in Individuals with ADHD: Prevalence, Impacts, Causes, and Treatments
1 Introduction
2 Overview of Sleep
3 Prevalence and Type of Sleep Problems in Children and Adolescents with ADHD
4 How Can Sleep Problems Be Measured?
5 What Is the Impact of Sleep Problems in Children and Adolescents with ADHD?
6 What Is the Etiology of Sleep Problems in Children and Adolescents with ADHD?
7 Sex Differences in Sleep Problems
8 Supporting Children and Adolescents with ADHD and sleep problems
8.1 Non-pharmacological Approaches
8.2 Pharmacological Approaches
9 Sleep in Adults with ADHD
10 Future Research and Clinical Directions
References
Obesity and Attention-Deficit Hyperactivity Disorder
1 Introduction
2 Obesity and ADHD
2.1 Causality
2.2 Shared Genetic and Neurobiological Underpinnings
3 Associations Between Behavioral Components of Obesity and ADHD
3.1 Eating Behavior
3.1.1 Loss-of-Control and Binge Eating
3.1.2 Eating in the Absence of Hunger
3.1.3 Ultra-Processed Food Consumption
3.2 Physical Activity
3.3 Sleep
4 Treatment Implications
4.1 Interventions Targeting Executive Functions
4.1.1 Digital Therapeutics
4.1.2 Episodic Future Thinking
4.2 Interventions Targeting Physical Activity
4.3 Medication
5 Summary and Future Directions
References
Genetics of Attention-Deficit Hyperactivity Disorder
1 Overview
2 Conceptualizing ADHD as a Trait
3 Heritability of ADHD
4 Rare Variants
5 Common Variants
6 Polygenic Risk Scores and Further Insights into Genetic Architecture
7 Genetic Discoveries and Insights into the Nature of ADHD
7.1 Developmental Change and Adult ADHD
7.2 Sex Differences
7.3 Relationship and Genetic Overlap with Other Neurodevelopmental Disorders
7.4 Relationship and Genetic Overlap with Other Psychiatric and Somatic Disorders
8 Biological Insights
9 Gene-Environment Interplay
10 Clinical Implications and Genetic Testing
11 Summary
References
Epigenetics and ADHD
1 Introduction
2 Overview of Epigenetic Mechanisms
2.1 DNA Methylation
2.2 Histone Modification
3 Overview of Epigenetics and ADHD
3.1 Candidate-Gene Studies
3.2 Epigenome-Wide Association Studies (EWAS)
4 Epigenetics at Birth Predicting Later ADHD
5 Twin Models
6 Environmental Exposure and Epigenetics in ADHD
7 Epigenetics and the ADHD Brain
8 Summary, Limitations and Future Directions
References
Preclinical Evaluation of Attention and Impulsivity Relevant to Determining ADHD Mechanisms and Treatments
1 Introduction
2 History of Attentional/Impulsivity Task Development in Rodents
3 Research Using Rodent Versions of CPT with Relevance to ADHD
3.1 5C-CPT for ADHD Research
3.2 rCPT for ADHD Research
4 Summary of the Benefits of Preclinical CPT-Like Tasks for ADHD Research
5 Is Measurement of Premature Responses Relevant to Impulsivity in ADHD?
6 Future Directions of Preclinical Attentional Research Using CPTs for ADHD
References
The Effects of Drug Treatments for ADHD in Measures of Cognitive Performance
1 Introduction
1.1 Clinical Symptomatology and Treatment
1.2 ADHD as an Opportunity for Translational Research
2 Effect of AMP, MPH, ATX in Preclinical Tests Related to Endophenotypes of ADHD
2.1 General Comment
2.2 Neurocognitive Endophenotypes to Study ADHD Drugs
2.3 Effects of AMP, MPH, and ATX on Measures Related to Attention
2.3.1 AMP and MPH
2.3.2 ATX
2.3.3 Summary
2.4 Effects of AMP, MPH, and ATX on Measures Related to Impulsivity
2.4.1 AMP
2.4.2 MPH
2.4.3 ATX
2.4.4 Summary
3 How Do the Preclinical Findings Translate to Clinical ADHD?
3.1 Subtypes of ADHD? (ADHD-I, ADHD-HI, ADHD-C)
3.2 How Do the Preclinical Effects of AMP, MPH, and ATX Translate to Clinic?
4 Final Comments
References
Animal Models of ADHD?
1 Introduction
2 Pioneer Animal Models of ADHD
2.1 The Neonatal 6-Hydroxydopamine (6-OHDA) Lesioned Rat
2.2 The Coloboma Mouse
2.3 The Dopamine Transporter Knockout (DAT-/-) Mouse
2.4 The Spontaneously Hypertensive Rat (SHR)
2.5 The Null Function NK1 Receptor-Gene Mouse (NK1R-/-)
2.5.1 NK1-/- Mice Express Hyperactivity, Inattention, and Motor Impulsivity
2.5.2 Other Aspects of the NK1R-/- Phenotype
2.5.3 NK1R-/- Mice: Pharmacological Challenges in the 5-CSRTT and 5C-CPT
2.5.4 A Portfolio of Biomarkers for TACR1 Vulnerability to ADHD?
3 Recent Models and Developments
References
Modelling ADHD-Like Phenotypes in Zebrafish
1 Introduction
2 Advantages and Limitations of Modelling ADHD in Zebrafish
3 Behavioral Tasks and Zebrafish Phenotypes Related to ADHD
3.1 Locomotion and Exploration
3.2 Attention Set Formation and Impulsivity
3.3 Other Comorbid Behaviors: Sociality, Aggression, and Risk-Taking Behavior
3.4 Other Comorbid Behaviors: Anxiety and Depression
4 Zebrafish Lines to Model ADHD Endophenotypes
5 Conclusions
References
What Has Been Learned from Using EEG Methods in Research of ADHD?
1 Introduction
2 Electromagnetic Imaging
3 Methods of Analysis
4 Resting State EEG
5 Event-Related EEG
6 Inhibitory Control
7 Error Processing
8 Cognitive Models of ADHD
9 Heterogeneity in ADHD
10 Endophenotypes: The Role of EEG in Explaining Heritability in ADHD
11 Future Directions
12 Conclusions
References
Alterations in Structural and Functional Connectivity in ADHD: Implications for Theories of ADHD
1 Introduction
1.1 Theories of Brain Connectivity in ADHD
1.1.1 The Default Mode Network Interference Hypothesis
1.1.2 Menon´s Multiple Network Hypothesis
2 Diffusion Tensor Imaging (DTI) Studies of ADHD
2.1 What Is DTI and How Is It Quantified?
2.2 DTI Methods
2.3 Region-of-Interest (ROI) Analysis
2.4 Tractography
2.5 Whole-Brain Voxel-Based Analysis
2.6 Whole-Brain DTI Meta-Analysis
2.6.1 van Ewijk et al. (2012)
2.6.2 Chen et al. (2016)
2.6.3 Aoki et al. (2018)
2.7 Conclusions of DTI Section
3 Resting-State Functional Connectivity Studies of ADHD
3.1 What Is Functional Connectivity and How Is It Quantified?
3.2 Heterogeneous Alterations in Functional Connectivity Across Primary Studies
3.3 Meta-Analyses of Resting-State Functional Connectivity Studies
3.3.1 Gao et al. (2019)
3.3.2 Sutcubasi et al. (2020)
3.3.3 Similarities and Differences Between the Meta-Analyses by Gao et al. (2019) and Sutcubasi et al. (2020)
3.3.4 Cortese et al. (2021)
3.4 Limitations of the Current Evidence Base on Functional Connectivity
3.5 Conclusions of Functional Connectivity Section
4 General Conclusions
References
Promising Developments in the Use of Induced Pluripotent Stem Cells in Research of ADHD
1 Introduction
2 Current Research Approaches for Investigating ADHD: Pros and Cons
3 Induced Pluripotent Stem Cells (iPSC): Potential Applications and Limitations
3.1 History and Evolution of Reprogramming Methods
3.2 The Use of Different Somatic Cells
4 Personalized Modelling of ADHD Genetic Subtypes for Molecular and Treatment-Response Studies
5 2D and 3D iPSC-Based Models
6 iPSC Technology in ADHD Research
7 Summary
References