Translating Decades of Neuroscience Research into Diagnostic and Treatment Biomarkers for ADHD.

In this chapter, we review scientific findings that form the basis for neuroimaging and neurophysiological biomarkers for ADHD diagnosis and treatment. We then highlight the different challenges in translating mechanistic findings into biomarkers for ADHD diagnosis and treatment. Population heterogeneity is a primary barrier for identifying biomarkers of ADHD diagnosis, which requires shifts toward dimensional approaches that identify clinically useful subgroups or prospective biomarkers that can identify trajectories of illness, function, or treatment response.

Where do neurodevelopmental conditions fit in transdiagnostic psychiatric frameworks? Incorporating a new neurodevelopmental spectrum.

Features of autism spectrum disorder, attention-deficit/hyperactivity disorder, learning disorders, intellectual disabilities, and communication and motor disorders usually emerge early in life and are associated with atypical neurodevelopment. These "neurodevelopmental conditions" are grouped together in the DSM-5 and ICD-11 to reflect their shared characteristics. Yet, reliance on categorical diagnoses poses significant challenges in both research and clinical settings (e.

Associations between polygenic risk scores for cardiometabolic phenotypes and adolescent depression and body dissatisfaction.

Background: Adolescents with elevated body mass index (BMI) are at an increased risk for depression and body dissatisfaction. Type 2 diabetes (T2D) is an established risk factor for depression. However, shared genetic risk between cardiometabolic conditions and mental health outcomes remains understudied in youth.

Measurement invariance of the Child Behavior Checklist (CBCL) across race/ethnicity and sex in the Adolescent Brain and Cognitive Development (ABCD) study.

There are numerous studies examining differences in the experience of disorders and symptoms of psychopathology in adolescents across racial or ethnic groups and sex. Though there is substantial research exploring potential factors that may influence these differences, few studies have considered the potential contribution of measurement properties to these differences. Therefore, this study examined whether there are differences across racial or ethnic groups and sex in the measurement of psychopathology, assessed in mother-reported behavior of 9-11 year old youth from the Adolescent Brain Cognitive Development study sample using updated Child Behavior Checklist scales (CBCL; Achenbach & Rescorla, 2001).

Alpha event-related decreases during encoding in adults with ADHD - An investigation of sustained attention and working memory processes.

Background: Executive functioning deficits are central to established neuropsychological models of ADHD. Oscillatory activity, particularly the alpha rhythm (8-12 Hz) has been associated with cognitive impairments in ADHD. However, most studies to date examined such neural mechanisms underlying executive dysfunction in children and adolescents with ADHD, raising the question of whether and to what extent those ADHD-related working memory impairments are still present in adults.

Do general and specific factors of preschool psychopathology predict preadolescent outcomes? A transdiagnostic hierarchical approach.

Background: Preschool psychiatric symptoms significantly increase the risk for long-term negative outcomes. Transdiagnostic hierarchical approaches that capture general ('p') and specific psychopathology dimensions are promising for understanding risk and predicting outcomes, but their predictive utility in young children is not well established. We delineated a hierarchical structure of preschool psychopathology dimensions and tested their ability to predict psychiatric disorders and functional impairment in preadolescence.

General . specific vulnerabilities: polygenic risk scores and higher-order psychopathology dimensions in the Adolescent Brain Cognitive Development (ABCD) Study.

Background: Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology.

The Etiological and Predictive Association Between ADHD and Cognitive Performance From Childhood to Young Adulthood.

Objective: Evidence about the etiology of the predictive associations between a diagnosis of ADHD and cognitive performance over time is scarce. Here, we examine these predictive and etiological patterns using a cross-lagged model design in a sample of 404 participants (74% males) from ADHD and control sibling pairs aged 6 to 17 years at baseline and 12 to 24 years at follow-up.

Methods: Data included IQ, short-term and working memory measures, and response speed and variability from a four-choice reaction-time task.

A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions.

A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs) and their co-occurrence with other conditions during childhood and adolescence remains incomplete. In the current meta-analysis, we synthesized the literature on (1) the contribution of genetic and environmental factors to NDDs, (2) the genetic and environmental overlap between different NDDs, and (3) the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). Searches were conducted across three platforms: Web of Science, Ovid Medline and Ovid Embase.

Taking stock of the present and looking to the future of ADHD research: a commentary on Sonuga-Barke et al. (2023).

The review by Sonuga-Barke and colleagues offers a thoughtful and wide-ranging appraisal of the current state of ADHD research, while also looking into the future to consider unresolved questions and critical next steps. Furthermore, it grapples with the tension between the need to define a coherent conceptualisation of ADHD for clinical and research purposes, while keeping an open mind to new research that challenges current consensus. In our commentary, we consider several cross-cutting ideas discussed in Sonuga-Barke et al.

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents.

Shared genetic influences between depression and conduct disorder in children and adolescents: A systematic review.

Introduction: The co-occurrence between major depression disorder (MDD) and conduct disorder (CD) is common across development and represents a significant risk factor for future psychiatric problems and long-term impairment. Large-scale quantitative genetic studies suggest that the MDD-CD co-occurrence may be partly explained by shared genetic vulnerability factors, in line with transdiagnostic models of psychopathology, but no systematic synthesis of the literature is currently available.

Methods: We therefore conducted a systematic review of the available genetic literature on the co-occurrence between MDD and CD in children and adolescents.

Treatment biomarkers for ADHD: Taking stock and moving forward.

The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery.

Electrophysiological and Clinical Predictors of Methylphenidate, Guanfacine, and Combined Treatment Outcomes in Children With Attention-Deficit/Hyperactivity Disorder.

Objective: The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.

Method: A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments.

Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder.

Objective: The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.

Method: A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination.

Event-related brain dynamics during mind wandering in attention-deficit/hyperactivity disorder: An experience-sampling approach.

Adults with attention-deficit/hyperactivity disorder (ADHD) report increased spontaneous mind wandering (MW) compared to control adults. Since MW is associated with ADHD severity and functional impairment, elucidating the brain mechanisms underlying MW may inform new interventions targeting MW and point to neural markers to monitor their efficacy. Population-based electroencephalographic (EEG) studies suggest that weaker event-related decreases in occipital alpha power characterise periods of MW, but no study has examined event-related brain oscillations during MW in individuals with ADHD.

Computationally-defined markers of uncertainty aversion predict emotional responses during a global pandemic.

Exposure to stressful life events involving threat and uncertainty often results in the development of anxiety. However, the factors that confer risk and resilience for anxiety following real world stress at a computational level remain unclear. We identified core components of uncertainty aversion moderating response to stress posed by the COVID-19 pandemic derived from computational modeling of decision making.

Brainmarker-I Differentially Predicts Remission to Various Attention-Deficit/Hyperactivity Disorder Treatments: A Discovery, Transfer, and Blinded Validation Study.

Background: Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates.

Methods: The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate (N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with sleep coaching (N = 136).

Event-related brain oscillations in attention-deficit/hyperactivity disorder (ADHD): A systematic review and meta-analysis.

Previous studies have associated attention-deficit/hyperactivity disorder (ADHD) with several alterations in electroencephalographic (EEG) activity. Time-frequency analyses capturing event-related power modulations are becoming an increasingly popular approach, but a systematic synthesis of the time-frequency literature in ADHD is currently lacking. We conducted the first systematic review and meta-analysis of time-frequency studies of children and adults with ADHD in comparison to neurotypical controls.

Neural signatures of data-driven psychopathology dimensions at the transition to adolescence.

Background: One of the challenges in human neuroscience is to uncover associations between brain organization and psychopathology in order to better understand the biological underpinnings of mental disorders. Here, we aimed to characterize the neural correlates of psychopathology dimensions obtained using two conceptually different data-driven approaches.

Methods: Dimensions of psychopathology that were either maximally dissociable or correlated were respectively extracted by independent component analysis (ICA) and exploratory factor analysis (EFA) applied to the Childhood Behavior Checklist items from 9- to 10-year-olds (n = 9983; 47.

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): III. Emotional dysfunction superspectrum.

The Hierarchical Taxonomy of Psychopathology (HiTOP) is a quantitative nosological system that addresses shortcomings of traditional mental disorder diagnoses, including arbitrary boundaries between psychopathology and normality, frequent disorder co-occurrence, substantial heterogeneity within disorders, and diagnostic unreliability over time and across clinicians. This paper reviews evidence on the validity and utility of the internalizing and somatoform spectra of HiTOP, which together provide support for an emotional dysfunction superspectrum. These spectra are composed of homogeneous symptom and maladaptive trait dimensions currently subsumed within multiple diagnostic classes, including depressive, anxiety, trauma-related, eating, bipolar, and somatic symptom disorders, as well as sexual dysfunction and aspects of personality disorders.

Connecting quantitatively derived personality-psychopathology models and neuroscience.

Traditionally, personality has been conceptualized in terms of of human experience - habitual ways of thinking, feeling, and behaving. By contrast, psychopathology has traditionally been conceptualized in terms of of disorder - disordered thinking, feeling, and behaving. The empirical literature, however, routinely shows that psychopathology does not coalesce into readily distinguishable categories.