Julie B. Schweitzer - US grants

DESCRIPTION (Adapted from applicant's abstract): Although Attention Deficit Hyperactivity Disorder (ADHD) is considered the most common child psychiatric disorder, little is known about the functional neurological deficits associated with this disorder. ADHD is now considered a chronic disorder in many affected individuals, with symptoms of overactivity, inattention, and impulsivity spanning from childhood through adulthood. As children these individuals are at-risk for academic failure and conduct problems. Adults who have retained the symptoms are more likely to experience occupational difficulties, abuse drugs, develop an antisocial personality disorder, and function less successfully in society. Functional neuroimaging techniques such as positron emission tomography (PET), that assess interactions between behavior and regional brain physiology may lead to the development of a better understanding of ADHD and more effective treatments. The objective of this Mentored Clinical Scientist Development Award is to develop the nominee's skills in applying functional neuroimaging techniques to better understand deficits in ADHD. The major goals of this award are to: 1) Develop into an independent researcher; 2) Study brain-environment interactions in ADHD; 3) Acquire expertise in functional neuroimaging techniques (i.e., PET) as it can be applied to ADHD; 4) Develop an independent laboratory studying brain-environment processes in ADHD. Skills acquired in the training program will be applied to pilot studies to assess the effect of task parameters and methylphenidate on regional cerebral blood flow (rCBF) in PET. Specific aims of the pilot studies are: 1) To assess the effect of practice on rCBF and task performance in ADHD and Control adults; 2) To examine how chronic methylphenidate administration in ADHD adults modulates the effects of practice on task performance and rCBF; 3) Establish further areas of study for the postaward phase for the candidate.

DESCRIPTION (provided by applicant): Impairments in working memory create difficulties for individuals with ADHD in their academic, social, and occupational activities. The overall hypothesis of this application is that individuals with ADHD engage an altered neural system when performing working memory tasks. This altered system arises as a consequence of an impaired executive system, which is subserved by the anterior cingulate (ACC) and prefrontal cortical regions (PFC). Impaired executive functioning weakens the ability to recruit subsidiary brain regions and strategies that support working memory. Functional imaging techniques give us a window into the neural basis of those strategies. Our imaging data suggest that phonological rehearsal strategies and the brain regions subserving them are impaired in ADHD. Visual-spatial strategies and their associated neural networks, are however, intact. Limited access to both phonological and visual strategies may increase errors and processing speed. We propose the following aims to investigate working memory in children with ADHD: 1) Define the neural correlates of working memory deficits in ADHD children using subtraction techniques in conjunction with a visual serial addition task; 2) Identify the relationship between BOLD signal changes generated during a working memory task and behavior (response time, error type; classroom ratings); and 3) Compare ADHD children with the Combined subtype to Inattentive subtype to identify the working memory neural strategies associated with each. We hypothesize that a general pattern will emerge in which ADHD combined type subjects use a predominantly visual-spatial strategy to perform a working memory serial addition task. The degree of ADHD dysfunction in the natural setting is expected to positively relate to visualspatial activation and negatively to prefrontal cortical activation. We predict that the ADHD-inattentive type will not exhibit the same level of visual-spatial activation during task performance as the Combined-type. Instead they will exhibit reduced activation in the same regions activated by the normal control children. A better understanding of strategies used in ADHD has potential educational implications for how children with ADHD learn and targets for treatment.

DESCRIPTION (provided by applicant): Problems with self-control are of major

Problems with self-control are of major

The proposed UC Davis ECHO ReCHARGE Study will follow a cohort of children last seen at ages 2-5 years (?baseline?) to determine environmental chemical and non-chemical stressors and resiliency factors that are associated with neurodevelopmental outcomes at ages 8-12 years (pre-adolescent) and 15-19 years (mid- to late adolescence). This project leverages the resources of the CHARGE (Childhood Autism Risks from Genes and Environment) Study, which, since 2003, has been enrolling three groups aged 2-5 years: children with autism spectrum disorder (ASD), children with other developmental delays (DD) and children from the general population with typical development (TD). These three groups, the ReCHARGE cohort, will be examined for the following outcomes of interest: attention deficit or hyperactivity symptoms; changes in cognitive or adaptive function; changes in severity or diagnosis; and symptoms of anxiety or depression. Pilot testing will take place in the UG3 phase, and in the UH3 phase, all will be examined either in pre-adolescence or mid- to late adolescence. The primary exposures of interest are pesticides, metals, air pollution, phthalates, nutrients, neighborhood characteristics, and family factors. Additionally, three mechanistic studies are proposed: an investigation of intergenerational epigenetic profiles; method development for metals analysis in dried blood spots; and sex specific associations of adrenal hormones with depressive symptoms. Approximately 1400 families are eligible for ReCHARGE, providing a robust sample for examination of main effects, interaction and mediation analyses. As part of the ECHO consortium, the ReCHARGE team will participate in the synthetic cohort combining children from multiple sites, and the cluster of studies focused on neurodevelopment in harmonizing protocols for the prospective UH3 phase and in seeking to analyze retrospective samples and data collaboratively, where feasible. During the UG3 phase, the ReCHARGE team will develop protocols, pilot test methods for recontacting and recruiting, for epigenetics in saliva vs. blood, and for implementation of the adrenal hormone study, including ways to increase compliance. Unique features of ReCHARGE include the contribution to understanding life course development in children with two different types of disabilities, and a novel model of adrenal hormone relationships with sex-specific affective disorders.

DESCRIPTION: Problems with impulsivity are of major

Distraction is a growing and large public health problem with estimated societal harm due to distracted driving alone at $123 billion1. In the age of texting, social media and computer pop-ups, distractions are unavoidable. There are no known interventions specifically developed to reduce distractions from interfering with attention. This project will test a treatment that combines virtual reality (VR) technology with habituation learning and exposure therapy to reduce the ability of distractors to interfere with learning and attention in children who are highly susceptible to being distracted. We will test the treatment in children with symptoms of attention- deficit/hyperactivity disorder (ADHD) as they represent an enriched sample experiencing impairing distractibility that interferes with their daily functioning. We hypothesize that children who suffer from severe distractibility can learn to ignore the distractors and improve their attention in VR therapy that simulates environments requiring focused attention. Our neural targets are both proactive and reactive control mechanisms used to suppress distractor processing. We will assess how well VR therapy is at modulating distractor suppression via saccade metrics and measure the frequency of oculomotor capture by distractors as well as the efficiency of distractor suppression before and after therapy. Changes in head movement toward distractors, parent and teacher ADHD rating scales and improved performance on attention-demanding tasks will further assess success of the therapy and its ability to generalize to novel environments. Children will practice computer exercises at home using a VR headset that simulates a classroom environment with a high rate of distractors. Children will be performing attention-demanding tasks as if they were in a classroom with the intensity and rate of presentation of the personalized distractions (e.g., peers talking, teacher walking by) adapted according to the child?s performance. With today?s low-cost VR-gaming technology, children will be able to participate in habituation treatment sessions at-home, several times a week, using a lightweight and comfortable VR gaming headset. In this ?fast fail? test of the VR therapy, the R61 phase will assess the preliminary success and feasibility of VR training to modify saccades to distractors in an adaptive training versus waitlist control trial. The R33 phase will commence if the R61 trial results indicate saccade metrics change in response to the VR treatment. Consistent with the RFA, the R33 will test the link between the degree of the VR therapy?s target engagement and functional outcomes (parent & teacher ratings) and feasibility. The R33 will compare an adaptive distractor training, non-adaptive distractor training and a waitlist control arm in children with high rates of distractibility. Data from this trial will determine whether to go forward for a subsequent confirmatory study in a larger, R01 project. Future studies will include new VR scenarios besides the classroom and a longer test of maintenance effects of the therapy. This project is consistent with the NIMH Strategic Plan: Objective 3: Strive for Prevention and Cures,? by developing new precision treatments based on neuroscience and behavioral science.

Fidgeting is a highly common behavior, with excessive fidgeting associated with attention-deficit/hyperactivity disorder (ADHD). Studies from our laboratory (1) and colleagues (2) suggest physical movement can enhance cognitive performance in children with ADHD. Hyper-sensorimotor behavior may be related to impaired regulation of arousal in the noradrenergic and dopaminergic systems (3). This project will assess if frequency and characteristics of sensorimotor behavior relates to cognitive and emotional response in adults with ADHD, in a fine-grained manner, unlike other studies. We will test if intrinsic fidgeting (Aim 1) and access to a specially designed fidget device (Aim 2) modulates behavioral and physiological response in cognitively and emotionally-demanding contexts. The hype of the commercially available Fidget Cube, its competitors and fidget spinners suggest it might, but there is no systematic evidence to inform consumers, a gap, we aim to fill. ADHD is a significant problem in adulthood, with estimates of 4.4% in the population (4). It is associated with higher rates of substance use disorders, traffic accidents and employment challenges and a national annual economic impact ranging from $143 to $266 billion (5). While overt hyperactivity is mostly associated with childhood, subtler, finer-grained frequent movements (e.g., leg movements, doodling, clicking objects, tapping) are highly common in adult ADHD. Little is known about the characteristics of fidgeting in adulthood or whether it can be harnessed to enhance self-regulation with the use of an external device. Our aims are as follows: Aim 1: Assess in a randomized controlled study if a) intrinsic fidgeting and b) use of a smart fidget device improves attention, working memory, processing speed and emotional regulation in adult ADHD; Aim 2: Identify specific touch characteristics associated with cognitive and emotional regulation in adult ADHD using behavioral coding and a prototype fidget ball (developed by Co-I Isbister) with embedded pressure sensors on the fidget surface transmitting real time data to a computer for data analysis; Exploratory Aim 3: Conduct a machine learning analysis of fidgeting behavior in relation to cognitive performance and emotional regulation to: 1) automate recognition of touch features present in fidgeting in adult ADHD; 2) correlate touch sequences with cognitive performance measures and; 3) recommend fidgeting strategies that should prove effective in a given situation. This project will build upon prior work by PI Schweitzer, with her expertise in ADHD, clinical translational research and cognitive neuroscience and Co-I Isbister, with expertise in computer science and engineering, who developed sensor-enabled, smart fidget devices with the goal of improving self-regulation of mood and attention (6-9); Co-I Shapiro (10) with machine learning expertise in analyzing fidgeting behavior. This project is highly responsive to NIMH Strategic Plan Objective 3 as it will inform researchers working to develop new interventions based on behavioral and physiological markers, tailored to the individual.

Abstract ? Parent Grant The proposed UC Davis ECHO ReCHARGE Study will follow a cohort of children last seen at ages 2-5 years (`baseline') to determine environmental chemical and non-chemical stressors and resiliency factors that are associated with neurodevelopmental outcomes at ages 8-12 years (pre-adolescent) and 15-19 years (mid- to late adolescence). This project leverages the resources of the CHARGE (Childhood Autism Risks from Genes and Environment) Study, which, since 2003, has been enrolling three groups aged 2-5 years: children with autism spectrum disorder (ASD), children with other developmental delays (DD) and children from the general population with typical development (TD). These three groups, the ReCHARGE cohort, will be examined for the following outcomes of interest: attention deficit or hyperactivity symptoms; changes in cognitive or adaptive function; changes in severity or diagnosis; and symptoms of anxiety or depression. Pilot testing will take place in the UG3 phase, and in the UH3 phase, all will be examined either in pre-adolescence or mid- to late adolescence. The primary exposures of interest are pesticides, metals, air pollution, phthalates, nutrients, neighborhood characteristics, and family factors. Additionally, three mechanistic studies are proposed: an investigation of intergenerational epigenetic profiles; method development for metals analysis in dried blood spots; and sex specific associations of adrenal hormones with depressive symptoms. Approximately 1400 families are eligible for ReCHARGE, providing a robust sample for examination of main effects, interaction and mediation analyses. As part of the ECHO consortium, the ReCHARGE team will participate in the synthetic cohort combining children from multiple sites, and the cluster of studies focused on neurodevelopment in harmonizing protocols for the prospective UH3 phase and in seeking to analyze retrospective samples and data collaboratively, where feasible. During the UG3 phase, the ReCHARGE team will develop protocols, pilot test methods for recontacting and recruiting, for epigenetics in saliva vs. blood, and for implementation of the adrenal hormone study, including ways to increase compliance. Unique features of ReCHARGE include the contribution to understanding life course development in children with two different types of disabilities, and a novel model of adrenal hormone relationships with sex-specific affective disorders.