Chandan J. Vaidya, Ph.D. - US grants

With National Science Foundation support, Dr. Vaidya will conduct a year long investigation of the role, across stages of human development, of specific brain regions in mediating the ability to consciously record, retain, and recall past experience. Late childhood is marked by rapid mastery of a variety of cognitive skills that are instrumental to educational, emotional, and social development. One such cognitive skill is declarative memory, the ability to consciously record, retain, and recall past experience. Between the ages of 7 and 13 years, the human brain undergoes profound physical changes that are thought to underlie improved memory abilities. These childhood years are also marked by a great amount of individual variation such that children of the same age differ considerably in the level of memory performance. Currently, there is little understanding of what specific brain changes mediate memory skills in childhood. Dr. Vaidya's study examines how neural networks mediating memory for verbal materials differ in individuals of different ages and in individuals of the same age but different levels of memory performance. Her study examines the role of two brain regions, medial temporal lobe and prefrontal cortex, in mediating memory in 7-9 year old children, 11-13 year old children, and 20-22 year old adults. Functional magnetic resonance imaging is used to examine brain activity related to memories strengthened by the use of strategies and memories simply forgotten.

The findings in this study are expected to lead to important information about the neurobiology of memory development. This work will advance the understanding of brain function and organization and its role in individual and developmental differences in a primary form of memory. This work is also likely to have implications for understanding the effects of closed head injury in individuals of different age.

behavioral genetics; methylphenidate; neural information processing; middle childhood (6-11); neurophysiology; attention deficit disorder; brain imaging /visualization /scanning; brain morphology; functional magnetic resonance imaging; phenotype; psychopharmacology; dopamine transporter; brain mapping; genotype; neural inhibition; short term memory; patient oriented research; human subject; clinical research; behavioral /social science research tag; bioimaging /biomedical imaging;

CRISP; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Facial Expression; Funding; Grant; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous; Patients; Process; Research; Research Personnel; Research Resources; Researchers; Resources; Schizophrenia; Schizophrenic Disorders; Source; United States National Institutes of Health; dementia praecox; emotional expression; expression of emotion; face expression; neural; relating to nervous system; schizophrenic; showing emotion

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is an NIMH-funded and IRB approved protocol. 288 subjects between the ages of 7 and 25 will be recruited from Dr. Vaidya's patient lists and by flyers. Half of the participants (72 female and 72 male) will have attention deficit hyperactivity disorder (ADHD) treated with stimulant drugs for at least 1 year. Their diagnosis will be confirmed by DSM-IV criteria, BCSC and ADHD Rating Scales. The healthy, non-ADHD control group will have 72 female and 72 male participants who will be age and IQ matched. Participants will be excluded if they have internalizing or externalizing scores on the Childhood Behavior Checklist, or if they have any history of prior psychological therapy or psychoactive drug treatment. 100 subjects per year will be studied in YEARs 1 and 2, and 88 in YEAR 3.

ABSTRACT Autism Spectrum Disorder (ASD) is characterized by pervasive socio-emotional and cognitive deficits even in children with high intellectual function. Its neuropathophysiology involves executive dysfunction mediated by prefrontal cortex but is not well-understood, due to high phenotypic heterogeneity and comorbidity with attention and anxiety disorders and a lack of resolution in affected component processes of executive function. We postulate that symptom expression varies among ASD children due to the influence of traits that characterize comorbid disorders (impulsivity, anxiety). Examining differences in functional brain organization of executive control due to anxiety and impulsivity with sensitive fMRI probes will elucidate phenotypic heterogeneity in ASD children. Guided by developmental neuroanatomical models, we will examine multiple top-down control processes and bottom-up perceptual processes that function in adaptive balance to serve goal-directed behavior. We will test the hypothesis that specific prefrontal-striato- limbic circuits, which mediate that adaptive balance, are atypical in ASD. We will manipulate component operations of top-down (voluntary, involuntary) and bottom-up (attention bias to salience) processing in 9-12 year-old high-functioning ASD children and age, Verbal IQ, and gender matched controls. Group differences and individual variation by anxiety, impulsivity, and symptom severity will be examined with confirmatory (hypothesis-driven) and exploratory (data-driven) analysis of functional networks and underlying white-matter microstructure. Aim I examines whether voluntary and involuntary control of attention is modulated by stimulus saliency (i.e., perceptual novelty, emotion) atypically in ASD. Exp 1 will examine incidental (involuntary) and intentional (voluntary) encoding of salient (novel/infrequent vs. familiar/repeated) distracters in the context of an ongoing task. Exp 2 will examine exogenous (involuntary) and endogenous (voluntary) attentional bias to salient faces (angry vs. neutral) in the Dot-probe task. Aim 2 examines whether voluntary and involuntary control of responses is modulated by stimulus domain (social-emotional or non- social) atypically in ASD. Exp 3 will examine voluntary response control (response inhibition and interference suppression) and involuntary context adaptation during a Flanker task with symbolic (non-social) stimuli. Exp 4 will examine voluntary response control during conflict varying in socio-emotional significance in a Stroop-like task. Aim 3 will examine whether intrinsic resting-state connectivity is atypical in ASD. Current research shows parallel functional organization during behavioral and resting states. We will search for resting-state correlates of component operations of executive control pooled by voluntary and involuntary conditions and domains (non-social, socio-emotional) from Exps 1-4 and determine whether they are atypical in ASD and vary by anxiety, impulsivity, and symptom severity. New knowledge from this proposal will refine models of ASD neuropathophysiology and provide targets for pharmacological and behavioral intervention.

DESCRIPTION (provided by applicant): An important source of individual variability in brain function supporting executive control is genetic variability in dopamine (DA) regulation. Extracellular DA levels vary by functional polymorphisms of clearance mechanisms: COMT (catechol-O-methyltransferase), an enzyme that degrades DA primarily in prefrontal cortex (PFC), has two genetic variants (Val, Met), and DAT (dopamine transporter), a protein that re-uptakes dopamine following release primarily in the striatum, has two common genetic variants (10-repeat, 9-repeat). Consistent with the importance of PFC-striatal circuits for executive operations such as working memory, independent, interactive, and additive effects of the two polymorphisms are apparent in functional activation during working memory. However, whether those genetic differences extend to functional connectivity during task performance and in the task-free, "resting state" is unknown. Slow spontaneous neural activity during rest (task-free state) is organized in networks comprising temporally correlated regions whose topography overlaps with task-evoked functional organization. The integrity of these networks predicts healthy attentional control and is disrupted in psychiatric disorders with executive dysfunction such as Schizophrenia and ADHD whose pathogenesis involves COMT and DAT genotypes, respectively. Thus, knowledge about genetic variability in healthy resting-state connectivity is important for suggesting neuroanatomical mechanisms of vulnerability to cognitive impairment associated with those disorders. We hypothesize that effects of COMT and DAT genotypes on functional connectivity will be paralleled in the task-evoked and resting- state in three networks, the task-negative network (default-mode) and two task-positive networks (executive control and salience). Healthy adults with combinations of COMT (Val/Val, Val/Met, Met/Met) and DAT (10/10, 9/10, 9/9) alleles will undergo fMRI during working memory (2-back vs. fixation) and during 5 mins of rest. Specific Aim 1 will examine differences by COMT and DAT alleles in activated (task-positive networks) and deactivated (task-negative network) regions and functional connectivity within each during working memory. We will examine independent and interactive (COMT X DAT ANOVA) and additive (regression analysis) effects of the genotypes. Specific Aim 2 will examine differences by COMT and DAT alleles in resting-state functional connectivity identified using seeds derived from Aim 1 (in confirmatory analysis) as well as using model-free Independent Components Analysis (in exploratory analysis), in collaboration with Dr. Vinod Menon. We expect to identify the same 3 networks as in Aim 1: 1) The task-negative network (medial PFC-posterior cingulate-hippocampus);2) Executive control network (dorsolateral PFC-lateral parietal);and 3) Salience network (anterior cingulate-insula-limbic). In both analyses, we will test for genotype differences as in Aim 1. These findings will be informative by extending current knowledge (connectivity during task-states) and breaking new ground (connectivity during resting-state). PUBLIC HEALTH RELEVANCE: This project aims to elucidate individual differences in functional brain organization and integrity of resting state connectivity associated with two genes controlling levels of dopamine, COMT Val158Met (catechol-O- methyltransferase) and DAT (dopamine transporter) in healthy adults. It will use functional magnetic resonance imaging to characterize brain activation and functional connectivity during working memory and while subjects rest with eyes closed. Knowledge gained from the proposed studies will suggest neuroanatomical hypotheses about vulnerability to cognitive dysfunction in disorders characterized by resting- state disturbances and associated with COMT and DAT such as Schizophrenia and Attention Deficit Hyperactivity Disorder, respectively.

? DESCRIPTION (provided by applicant): The purpose of this exploratory proposal is to examine effects of bariatric surgery, specifically vertical sleeve gastrectomy, on functional and structural neural and cognitive function in adolescents aged 14-21 years. While obese adults face serious risk of poor health outcomes (cardiovascular, metabolic, musculoskeletal, respiratory, cancer), obese children bear the added burden of poor academic and psychosocial functioning, setting them on maladaptive developmental trajectories resulting in high social and economic costs to the person and the nation. Adolescence is a critical period for maturation of executive and motivational functioning, and severe obesity during this period puts youth at far greater risk for poor physical and psychological outcomes. Bariatric surgery as a treatment option is increasingly being adopted, with proven weight loss (13%-68% excess weight loss in 3-12 months post-surgery in our cohort) and improved metabolic and cardiovascular health. Whether cognitive and brain health also improve is an open question. The proposal will address this gap by taking advantage of the opportunity presented by adolescents who are already undergoing bariatric surgery at Children's National Medical Center. The proposal focuses on three areas of function known to be affected in pediatric obesity: executive function that depends on prefrontal cortes, long-term memory that depends on hippocampus and surrounding regions (medial temporal lobe), and reward function associated with ventral striatum. Aim 1 will test the hypothesis that executive function, verbal and visual memory, and reward sensitivity will improve following surgery. Aim 2 will test the hypothesis that functional activation and connectivity of prefrontal, medial temporal lobe, and ventral striatal regions will improve following surgery, using functional magnetic resonance imaging (fMRI). Lastly, Aim 3 will explore whether the magnitude of weight-loss induced change in metabolic indices (e.g., insulin resistance) mediates association between changes in neural correlates and cognitive function. Fifty adolescents who are candidates for surgery will undergo testing twice, 25 at a minimum of one month before surgery and then again 4 months after surgery, and 25 who have had their surgery delayed for insurance or other reasons who will be tested twice 4-5 months apart; in addition a non-obese control group of 25 adolescents matched for age and gender will also be tested twice at the same intervals. While Aim 1 and 2 seek initial evidence for impact of rapid weight loss on brain and cognitive function, Aim 3 will generate hypotheses about potential metabolic sources of functional neural effects of weight loss to be tested in future work. These findings will further understanding of the influence of the gut on brain and cognition at a critica time in development, by providing neurocognitive markers sensitive to metabolic health that can be used to test mechanistic hypotheses in future work.

Abstract The supplement requests extension of funding for one year following the end of the parent grant on 4/30/2021, to offset disruption of data collection progress due to covid.