The science of attention-deficit/hyperactivity disorder (ADHD) is motivated by a translational goal - the discovery and exploitation of knowledge about the nature of ADHD to the benefit of those individuals whose lives it affects. Over the past fifty years, scientific research has made enormous strides in characterizing the ADHD condition and in understanding its correlates and causes. However, the translation of these scientific insights into clinical benefits has been limited. In this review, we provide a selective and focused survey of the scientific field of ADHD, providing our personal perspectives on what constitutes the scientific consensus, important new leads to be highlighted, and the key outstanding questions to be addressed going forward. We cover two broad domains - clinical characterization and, risk factors, causal processes and neuro-biological pathways. Part one focuses on the developmental course of ADHD, co-occurring characteristics and conditions, and the functional impact of living with ADHD - including impairment, quality of life, and stigma. In part two, we explore genetic and environmental influences and putative mediating brain processes. In the final section, we reflect on the future of the ADHD construct in the light of cross-cutting scientific themes and recent conceptual reformulations that cast ADHD traits as part of a broader spectrum of neurodivergence.

Annual Research Review: Perspectives on progress in ADHD science - from characterization to cause.

Viloxazine (QELBREE™), a selective norepinephrine reuptake inhibitor, is being developed by Supernus Pharmaceuticals as a non-stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients. This is a novel formulation of a pharmacological agent formerly marketed in Europe for the treatment of depression in adults. Viloxazine received its first pediatric approval in April 2021 in the USA for the treatment of ADHD in pediatric patients aged 6–17 years. Approval was based on positive results from a series of short-term phase III clinical trials in which viloxazine improved the severity of ADHD symptoms in children and adolescents with diagnosed ADHD. Viloxazine is available as extended-release capsules for once-daily oral administration. This article summarizes the milestones in the development of viloxazine leading to this first pediatric approval for ADHD.

Viloxazine: Pediatric First Approval.

Research has linked executive function (EF) deficits to many of the behavioral symptoms of attention deficit hyperactivity disorder (ADHD). Evidence of the involvement of EF impairment in ADHD is corroborated by accumulating neuroimaging studies, specifically functional magnetic resonance imaging (fMRI) studies. However, in recent years, functional near-infrared spectroscopy (fNIRS) has become increasingly popular in ADHD research due to its portability, high ecological validity, resistance to motion artifacts, and cost-effectiveness. While numerous studies throughout the past decade have used fNIRS to examine alterations in neural correlates of EF in ADHD, a qualitative review of the reliability of these findings compared with those reported using gold-standard fMRI measurements does not yet exist. The current review aims to fill this gap in the literature by comparing the results generated from a qualitative review of fNIRS studies (children and adolescents ages 6–16 years old) to a meta-analysis of comparable fMRI studies and examining the extent to which the results of these studies align in the context of EF impairment in ADHD. The qualitative analysis of fNIRS studies of ADHD shows a consistent hypoactivity in the right prefrontal cortex in multiple EF tasks. The meta-analysis of fMRI data corroborates altered activity in this region and surrounding areas during EF tasks in ADHD compared with typically developing controls. These findings indicate that fNIRS is a promising functional brain imaging technology for examining alterations in cortical activity in ADHD. We also address the disadvantages of fNIRS, including limited spatial resolution compared with fMRI.

Functional near-infrared spectroscopy in developmental psychiatry: a review of attention deficit hyperactivity disorder.

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson’s disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. Significance Statement Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.

Dopamine, Immunity, and Disease

In this study, we proposed an analytical framework to identify dynamic task-based functional connectivity (FC) features as new biomarkers of emotional sensitivity in nursing students, by using a combination of unsupervised and supervised machine learning techniques. The dynamic FC was measured by functional Near-Infrared Spectroscopy (fNIRS), and computed using a sliding window correlation (SWC) analysis. A ${k}$ -means clustering technique was applied to derive four recurring connectivity states. The states were characterized by both graph theory and semi-metric analysis. Occurrence probability and state transition were extracted as dynamic FC network features, and a Random Forest (RF) classifier was implemented to detect emotional sensitivity. The proposed method was trialled on 39 nursing students and 19 registered nurses during decision-making, where we assumed registered nurses have developed strategies to cope with emotional sensitivity. Emotional stimuli were selected from International Affective Digitized Sound System (IADS) database. Experiment results showed that registered nurses demonstrated single dominant connectivity state of task-relevance, while nursing students displayed in two states and had higher level of task-irrelevant state connectivity. The results also showed that students were more susceptive to emotional stimuli, and the derived dynamic FC features provided a stronger discriminating power than heart rate variability (accuracy of 81.65% vs 71.03%) as biomarkers of emotional sensitivity. This work forms the first study to demonstrate the stability of fNIRS based dynamic FC states as a biomarker. In conclusion, the results support that the state distribution of dynamic FC could help reveal the differentiating factors between the nursing students and registered nurses during decision making, and it is anticipated that the biomarkers might be used as indicators when developing professional training related to emotional sensitivity.

Detection of Emotional Sensitivity Using fNIRS Based Dynamic Functional Connectivity

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting up to 5.3% of children and 2.5% of adults depending on the country considered. Current pharmacological tre...

https://www.tandfonline.com/doi/pdf/10.1080/14728214.2020.1820481

Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD).

Hemodynamic and behavioral peculiarities in response to emotional stimuli in children with attention deficit hyperactivity disorder: An fNIRS study.

Individual responses to methylphenidate (MPH) can significantly differ in children with attention-deficit/hyperactivity disorder (ADHD) in terms of the extent of clinical amelioration, optimal dosage needed, possible side effects, and short- and long-term duration of the benefits. In the present repeated-measures observational study, we undertook a proof-of-concept study to determine whether clustering analysis could be useful to characterize different clusters of responses to MPH in children with ADHD. We recruited 33 children with ADHD who underwent a comprehensive clinical, cognitive, and neurophysiological assessment before and after one month of MPH treatment. Symptomatology changes were assessed by parents and clinicians. The neuropsychological measures used comprised pen-and-paper and computerized tasks. Functional near-infrared spectroscopy was used to measure cortical hemodynamic activation during an attentional task. We developed an unsupervised machine learning algorithm to characterize the possible clusters of responses to MPH in our multimodal data. A symptomatology improvement was observed for both clinical and neuropsychological measures. Our model identified distinct clusters of amelioration that were related to symptom severity and visual-attentional performances. The present findings provide preliminary evidence that clustering analysis can potentially be useful in identifying different responses to MPH in children with ADHD, highlighting the importance of a personalized medicine approach within the clinical framework.

Erika Gatti

Papers

Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD).

Hemodynamic and behavioral peculiarities in response to emotional stimuli in children with attention deficit hyperactivity disorder: An fNIRS study.

Patterns of Response to Methylphenidate Administration in Children with ADHD: A Personalized Medicine Approach through Clustering Analysis