2012 — 2016 |
Acheson, Ashley Dougherty, Donald M [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Relating Brain Maturation to Impulse Control and Substance Use Development @ University of Texas Hlth Science Center
DESCRIPTION (provided by applicant): Adolescent substance use is common and associated with both significant negative individual consequences and substantial costs to society. The proposed study will capitalize on a cost-effective opportunity to identify neurobiological mechanisms underlying risks for, and consequences of, adolescent substance use. Tests will be conducted in adolescents with high (n= 68) and low (n = 34) familial risk for substance use disorders, selected from a larger ongoing longitudinal study that is testing causal relationships between the development of impulse control and substance use. In this new application, we seek to identify relationships between maturation of frontostriatal circuitry, impulse control development, and progression of substance use involvement across adolescence. We propose to measure frontostriatal circuitry in 11- to 14- year-old adolescents at risk for substance use disorders and to repeat assessments annually for a 5-year period. We will compare circuitry between adolescents at high or low risk for substance use disorders (based on family history) before regular drug use begins (Aim 1); determine how individual differences in early adolescent frontostriatal circuitry development, before regular drug use, predict onset and severity of substance use (Aim 2); and examine how trajectories of frontostriatal circuitry development are affected by both familial risk and adolescent substance use (Aim 3). This application posits that a) impulsive reward- focused behaviors emerging during adolescence are driven, at least in part, by inadequate regulation of the striatum due to delayed maturation of the prefrontal cortex, and b) that adolescents are uniquely vulnerable to substance use disorders and resultant cognitive impairments. This framework allows for testable hypotheses to examine neurobiological mechanisms underlying relationships observed between impulse control and substance use disorders across adolescent development. This is an opportunity to study the etiology of adolescent substance use by examining neurobiological mechanisms underlying risk for substance use disorders, impulse control development, and effects of substance use on adolescent brain development. Our study has the unique advantage of recruiting from an established and well-characterized cohort that is being followed longitudinally. A strong interdisciplinary research team is in place which combines unique expertise in substance abuse research, advanced imaging methodology, adolescent behavioral assessment, and statistical modeling. This proposal integrates distinct bodies of research on brain development, adolescent behavior, and substance abuse to advance understanding of risks and consequences of adolescent substance use.
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0.99 |
2014 — 2018 |
Acheson, Ashley Lovallo, William R [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Oklahoma Family Health Patterns: a Study Across Generations @ University of Oklahoma Hlth Sciences Ctr
DESCRIPTION (provided by applicant): The Oklahoma Family Health Patterns project is an intensive study of psychological, behavioral, and stress reactivity characteristics in healthy young adults with a family history of alcoholism (FH+) with a goal of identifying characteristics that place these persons at elevated risk for the disorder. We have recently identified early life adverse experience (ELA), including physical and sexual abuse and separation from parents, as occurring with disproportionate impact in FH+, and we have shown that ELA accounts for diminished stress reactivity, behavioral impulsivity, and poor mood regulation, all of which are risk factors for alcohol and other substance use disorders. The impact of ELA in the FH+ population demands to be studied further in a Gene x Environment interaction given the known positive feedbacks between FH+ and ELA. Our goal is to carry out a G x E interaction study by genotyping our FH x ELA and examining the impact of genotype on the broad range of personal characteristics currently under study in this project. Aim 1. Examine the differential impact of ELA on psychological and behavioral characteristics of FH+ vs. FH- groups using an expanded sample of volunteers. Aim 2. Use our larger sample to carry out a Gene x Environment analysis to test specific alleles that are strongly suspected of influencing activity in brain motivational systems, expanding on work we initiated with NIAAA thanks to a supplement to this R01 (AA012207-S1). Aim 3. Test specific aspects of temperament as endophenotypes linking FH and ELA to behavioral, cognitive, and stress reactivity as aspects of the person's phenotype. Aim 4. Increase our recruitment base by screening and testing volunteers at a second site, the University of Texas HSC, San Antonio, where we currently conduct our neuroimaging studies. Alcoholism is a costly burden to society, but risk factors for alcoholism are poorly understood. The vast majorities of studies focuses on alcoholic patients but are unable to disentangle preexisting influences from the effects of alcohol intake history. Our high-risk study design can be of value by contrasting FH+ and FH- with regard to environmental contributors and genetic vulnerabilities that contribute to behavioral risk factors.
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0.949 |
2021 |
Acheson, Ashley Mckelvey, Lorraine M (co-PI) [⬀] Ou, Xiawei |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
1/6 Hbcd Prenatal Experiences and Longitudinal Development (Prelude) Consortium @ Arkansas Children's Hospital Res Inst
PROJECT SUMMARY/ABSTRACT Brain development occurs at a rapid pace prenatally and throughout childhood, impacted by dynamic genetic and environmental influences. Studies using advanced neuroimaging have provided significant insights into brain development but have been limited by small sample size, especially for high-risk populations. Substance- exposed infants are at particularly high risk for adverse outcomes; however, findings are inconsistent, making it difficult to disentangle prenatal exposure effects from other adverse influences. The objectives of our HEALthy Brain and Child Development (HBCD) Prenatal Experiences and Longitudinal Development (PRELUDE) consortium are to characterize typical trajectories of brain development from birth through childhood, measuring the influence of key biologic and environmental factors and their interactions on child social, cognitive, and emotional development. We will assess how children prenatally exposed to opioids and other substances, as well as environmental adversity, differ in those brain trajectories and outcomes. Our consortium consists of six centers (Arkansas Children?s Research Institute, Case Western Reserve University, Cincinnati Children?s Hospital, Children?s National Medical Center, University of North Carolina at Chapel Hill, and Vanderbilt University) which have collaborated previously and have complementary expertise in neuroimaging, neurophysiology, longitudinal clinical research, child development, substance exposure and addiction, ethical/legal issues, and clinical care of high-risk infants/children. The PRELUDE consortium will recruit 680 pregnant women with substance use, 680 at-risk pregnant women without substance use, and 1360 comparison pregnant women representative of the general population to contribute to the overall HBCD study. We will work closely with the other sites, the HBCD Consortium Administrative Core, and the HBCD Data Coordinating Center to develop a comprehensive study protocol and ensure compliance of study workflow and data transfer. Our consortium has an optimized research protocol and 4 specific aims: 1) Employ ethical and evidence-based best practices to enroll and retain a diverse cohort of pregnant women into a longitudinal study of infant/child brain development, oversampling mothers from high-risk backgrounds and those using substances during pregnancy; 2) Engage a comprehensive array of maternal- and child-oriented community stakeholders to identify community concerns and priorities regarding this research, minimize risks, and promote long-term engagement of the recruited child-mother dyads; 3) Collect rich data to examine how maternal health context and broader environmental factors may affect the maternal-fetal dyad and neurodevelopment of children; 4) Capture key developmental windows during which maternal and environmental factors may interact with brain and behavioral development of children. The insights from these data will provide greater understanding of factors affecting early childhood brain development, allowing targeted interventions and improved outcomes for mother-child dyads.
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0.912 |
2021 |
Acheson, Ashley Kochunov, Peter V. (co-PI) [⬀] Lovallo, William R O'connor, Jason C (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Family Health Patterns: a Study Across Generations @ Univ of Arkansas For Med Scis
PROJECT SUMMARY Individuals with a family history of alcoholism (FH+) are 4 to 8 times more likely to develop an alcohol use disorder (AUD) compared to individuals with no such family histories. We developed the Family Health Patterns project to characterize risk-related phenotypic characteristics of FH+ young adults. During our recent funding period, we have identified robust links between increased early life adversity (ELA) in FH+ and their (a) blunted stress reactivity, (b) increased antisocial tendencies, (c) poor affect regulation, and (d) impaired cognitive performance. In our neuroimaging studies, we identified diffusivity changes in frontal white matter tracts in both FH+ young adults and children, suggesting decreased myelination and axon damage in underlying neural circuitry. We interpret these collective findings to suggest that increased ELA in FH+ individuals induces lasting neurobiological changes and consequent behavioral effects that increase AUD risk. To guide the present proposal, we developed a heuristic model of how ELA contributes to risk-related phenotypic characteristics in FH+ persons. We propose that convergent epigenetic and transcriptomic dysregulation of immune genes increase inflammation and immunoreactivity, thereby impairing myelination and/or damaging axons in developing frontal white matter tracts. The resulting impaired communication to and from the prefrontal cortex contributes to phenotypic characteristics of increased antisocial tendencies and poorer affect regulation and cognitive performance, increasing AUD risk. Here we propose to test this model by examining inflammatory gene expression, functional changes in immunoreactivity, and cerebral white matter myelin levels and axon damage markers in FH+ and FH? young adults. We will then examine relationships of these variables with ELA exposure and risk-related phenotypic characteristics. This proposal rigorously builds on our extensive findings on FH+ behavioral and biological phenotypes by testing a novel, overarching model of AUD risk. While extensive preclinical evidence exists illustrating ELA induces long-lasting dysregulation of the immune system and resulting neural and behavioral sequela, our proposal breaks new ground by comprehensively examining these relationships in humans using advanced immunology and multimodal neuroimaging together with in-depth behavioral and clinical assessments.
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0.918 |