Faculty Bibliography

Attention-Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition associated with impaired function and increased risk of poor outcomes in children, young people and adults with the condition. Currently approved pharmacological treatments for ADHD include a range of stimulant (methylphenidate, amphetamine) and nonstimulant (atomoxetine, guanfacine, clonidine) medications. All have been shown to be effective in treating the symptoms of ADHD and improving other functional outcomes including quality of life, academic performance, rates of accidents and injuries, and do not appear to be associated with significant adverse outcomes or side effects. In this chapter, we review medications for ADHD by summarising the mechanisms of action of each of the two main classes of compounds (stimulants and nonstimulants), the formulations of the most commonly prescribed medications within each class, their efficacy in treating ADHD symptoms and other outcomes, and other factors that influence treatment decisions including side effects and tolerability, comorbidities and medical history. We conclude with a summary of the treatment decisions made by clinicians and suggest some next steps for research. Further research is needed to understand the mechanisms of action of these medications and how exactly they improve symptoms, and to examine their effects on commonly occurring comorbidities.

This paper focuses on the problem of modeling and estimating interaction effects between covariates and a continuous treatment variable on an outcome, using a single-index regression. The primary motivation is to estimate an optimal individualized dose rule and individualized treatment effects. To model possibly nonlinear interaction effects between patients' covariates and a continuous treatment variable, we employ a two-dimensional penalized spline regression on an index-treatment domain, where the index is defined as a linear projection of the covariates. The method is illustrated using two applications as well as simulation experiments. A unique contribution of this work is in the parsimonious (single-index) parametrization specifically defined for the interaction effect term.

Frontal power asymmetry (FA), a measure of brain function derived from electroencephalography, is a potential biomarker for major depressive disorder (MDD). Though FA is functional in nature, it is typically reduced to a scalar value prior to analysis, possibly obscuring its relationship with MDD and leading to a number of studies that have provided contradictory results. To overcome this issue, we sought to fit a functional regression model to characterize the association between FA and MDD status, adjusting for age, sex, cognitive ability, and handedness using data from a large clinical study that included both MDD and healthy control (HC) subjects. Since nearly 40% of the observations are missing data on either FA or cognitive ability, we propose an extension of multiple imputation (MI) by chained equations that allows for the imputation of both scalar and functional data. We also propose an extension of Rubin's Rules for conducting valid inference in this setting. The proposed methods are evaluated in a simulation and applied to our FA data. For our FA data, a pooled analysis from the imputed data sets yielded similar results to those of the complete case analysis. We found that, among young females, HCs tended to have higher FA over the θ, α, and β frequency bands, but that the difference between HC and MDD subjects diminishes and ultimately reverses with age. For males, HCs tended to have higher FA in the β frequency band, regardless of age. Young male HCs had higher FA in the θ and α bands, but this difference diminishes with increasing age in the α band and ultimately reverses with increasing age in the θ band.

Current clinical literature and supporting animal literature have shown that repeated and profound early-life adversity, especially when experienced within the caregiver-infant dyad, disrupts the trajectory of brain development to induce later-life expression of maladaptive behavior and pathology. What is less well understood is the immediate impact of repeated adversity during early life with the caregiver, especially since attachment to the caregiver occurs regardless of the quality of care the infant received including experiences of trauma. The focus of the present manuscript is to review the current literature on infant trauma within attachment, with an emphasis on animal research to define mechanisms and translate developmental child research. Across species, the effects of repeated trauma with the attachment figure, are subtle in early life, but the presence of acute stress can uncover some pathology, as was highlighted by Bowlby and Ainsworth in the 1950s. Through rodent neurobehavioral literature we discuss the important role of repeated elevations in stress hormone corticosterone (CORT) in infancy, especially if paired with the mother (not when pups are alone) as targeting the amygdala and causal in infant pathology. We also show that following induced alterations, at baseline infants appear stable, although acute stress hormone elevation uncovers pathology in brain circuits important in emotion, social behavior, and fear. We suggest that a comprehensive understanding of the role of stress hormones during infant typical development and elevated CORT disruption of this typical development will provide insight into age-specific identification of trauma effects, as well as a better understanding of early markers of later-life pathology.