Plenary Sessions

Plenary Session #1
Epigenetics: Implications for Prevention Science

Wednesday, June 2, 2010, 8:30 am – 10:00 am,
Roundtable follows 10:15 am – 11:45 am

Chair: Ron Prinz, Ph.D. University of South Carolina
Presenters: Randy L. Jirtle, Ph.D., Department of Radiation Oncology, Duke University Medical Center, Durham, NC and Gustavo Turecki MD PhD, McGill Group for Suicide Studies, Department of Psychiatry, McGill University

Epigenetics, Imprinting and the Developmental Origins of Disease Susceptibility
Presenter: Randy L. Jirtle, Ph.D.

Human epidemiological and animal experimental data indicate that the risk of developing adult-onset diseases and neurological disorders is influenced by persistent adaptations to prenatal and early postnatal exposure to environmental conditions such as nutritional privation. Moreover, it is increasingly evident that the link between what we are exposed to in utero and disease formation in adulthood involves epigenetic modifications like DNA methylation and histone modifications at metastable epiallele and imprinted gene loci.

Genes with metastable epialleles have highly variable expression because of stochastic allelic changes in the epigenome rather than mutations in the genome. The viable yellow agouti (Avy) mouse harbors a metastable Agouti gene because of an upstream insertion of a transposable element. We have demonstrated in the Avy mouse that maternal dietary supplementation during pregnancy, with either methyl donors (i.e. folic acid, vitamin B12, choline and betaine) or genistein, alters coat color and decreases adult disease incidence in the offspring by increasing DNA methylation and altering histone marks at the Avy locus. Moreover, these nutritional supplements can counteract the negative effects on the epigenome caused by the endocrine disruptor, bisphenol A (BPA).

Genomic imprinting is an epigenetic form of gene regulation that results in monoallelic, parent-of-origin dependent gene expression. Since imprinted genes are functionally haploid, only a single genetic or epigenetic event is needed to dysregulate their function. This unique vulnerability means that imprinted genes are prime candidates for causative roles in human diseases that have a parental inheritance bias and an environmental component in their formation. Utilizing computer-learning algorithms, we predict that humans have fewer imprinted genes than mice, and that there is only a mere 30% overlap between their imprinted gene repertoires. Thus, mice may not be a suitable choice for studying diseases resulting primarily from the deregulation of genomic imprinting. We are now poised to determine the role of epigenetics in the etiology of human conditions such as autism, cancer, diabetes, obesity, and schizophrenia. (Supported by NIH grants ES13053, ES08823, ES015165 and T32-ES07031, and DOE grant DE-FG02-05ER64101)

The Relationship Between Early Life Adversity and Suicide Risk: From Molecules to Behavior
Presenter: Gustavo Turecki MD PhD

Among factors associated with early adversity, childhood abuse and neglect are one of the strongest predictors of major depression and suicidality. Childhood sexual abuse, in particular, is associated with earlier age of onset of depression, chronic course and more severe depressive outcome. Moreover, history of childhood sexual abuse increases the odds of suicidal behavior up to 12 times. Although less consistently, physical abuse and neglect during childhood are also found to modify risk for depression onset, course, severity and associated suicidality. A pivotal question, however, is how does childhood adversity influence the risk – many years later – of major depressive episodes and suicidal behavior? In addition, an important question is what are the molecular mechanisms that are involved in this process? Dr. Turecki will address these questions during his presentation. He will present recent data suggesting that epigenetic mechanisms, particularly focusing on glucocorticoid promoter methylation, may, at least in part, help explain why certain individuals who have been abused during childhood are at an increased risk of depression and suicide. This is consistent with data from animal studies, which have recently given us important insight into some of the epigenetic processes that modify behavior and result from early social environmental experiences. Subsequently, he will discuss behavioral mediators of suicide risk, particularly focusing on the role of high anxiety traits, HPA dysregulation and impulsive-aggressive behaviors. These results will be discussed in terms of a general conceptual framework for the understanding of suicide risk.

Plenary Session #2
Psychosocial and Environmental Influences on Brain Development and Psychopathology

Thursday, June 3, 2010, 8:30 am-10:00 am,
Roundtable follows 10:15 am-11:45 am

Chair: Diana Fishbein, RTI
Presenters: Deborah Yurgelun-Todd, PhD, University of Utah, Monique Ernst, NIMH, Susan Andersen, PhD, McLean Hospital/Harvard Medical School.

Research has established that individual differences in risk for psychopathologies can only be thoroughly understood by recognizing that human orientation to and processing of environmental inputs rely heavily upon genetic and neurobiological mechanisms. In turn, environmental factors can alter genetic and epigenetic processes which further modify environmental responses. Interactions between these underlying mechanisms and exposure to a nurturing versus adverse environment bias the developmental trajectories of behavior toward favorable or psychopathological outcomes. A parallel body of research indicates that the neural dysfunctions that often underlie psychopathology, regardless of their origins, are malleable. Moreover, mechanisms that compensate for these neural and behavioral problems can be strengthened by appropriate psychosocial (e.g., nurturing environments, educational and enrichment programs, cognitive neurorehabilitation, exposure therapy, mindful yoga, etc.), and technological (e.g., virtual reality, adaptive training systems, robotic devices, etc.) interventions. Findings of this nature have extraordinary potential significance for mental and public health programs and policies.

Human Brain Development and the Onset of Cannabis Abuse
Presenter: Deborah Yurgelun-Todd, Ph.D.

The relationship among psychosocial factors, environment, and brain development is dynamic. While environmental and psychosocial pressures contribute directly to brain development, the trajectory of normal brain development itself shapes how psychosocial and environmental information is processed. We have applied magnetic resonance techniques to study neural development through the application of multiple neuroimaging approaches in combination with neurocognitive and laboratory measures of affect. We have also used this strategy to examine altered brain development associated with substance abuse in adolescence and early adulthood. Our research indicates an overlap between brain systems that are sensitive to psychosocial and environmental information during normal development and those that are affected by clinical pathology and substance abuse. Functional connectivity data showing the impact of age and gender will be shown for both healthy non-using and substance using adolescents. In addition, imaging and neuropsychological data will be presented describing decision making and impulsivity in adolescents in relationship to cannabis abuse and psychopathology. The data suggest that neurobiologic factors may contribute to the onset of substance abuse as well as be associated with the effects of continued substance abuse. These results have important implications for prevention strategies suggesting that programs that emphasize the development and strengthening of limbic and cortical circuits may enhance executive functions and resilience thus reducing the initiation of substance abuse.

Bridging Neurodevelopmental Science and Public Health
Presenter: Monique Ernst, MD, PhD

The past two decades have witnessed an explosion of growth in the neurosciences, particularly with regards to the development of neural systems. Paradoxically, to date, this work has had little impact on prevention, treatment, or policy, despite potentially enormous opportunities at the interface between developmental neuroscience and approaches to improve public health. This presentation will describe developmental trajectories of neural systems. Special emphasis will be placed on the period of adolescence, which is recognized as one of the most vulnerable periods of development with respect to the emergence of risk-taking behavior and its disastrous consequences, drug use, and peak onset of affective disorders. A number of neural systems models have been proposed as frameworks to understand how cognitive, affective and social influences can precipitate, as well as protect against, behavioral and emotional health problems. One such model theorizes an asynchrony in the development of inhibitory systems and reward systems. A more general proposal posits similar maturational imbalances among cognitive, affective and motivational systems. An additional level of complexity comes with the drastic hormonal changes that accompany puberty, and which modulate neural circuitries in critical ways. The presentation of these various neurodevelopmental themes leverages the question of what are the most common modifiable aspects of development that could be targeted in ways that improve the trajectory of cognitive, social and emotional development. In broad terms, how can we facilitate the bridge between neuroscience findings and public health, including public thinking and discussion of policy?

Psychosocial and Environmental Influences on Brain Development and Psychopathology
Presenter: Susan L. Andersen, Ph.D.

Brain development is a complex process, with many different levels of interaction that will eventually culminate in functional neural systems working together to produce behavior that is appropriate to the environment. While genes set the stage, experience shapes the development of this highly adaptive organ, and it is here, that numerous psychiatric illnesses can be traced to developmental processes gone awry. However, a multi-level approach is needed to understand how these processes unfold with maturation. Information from clinical and preclinical studies must inform each other in ways that speak a common language, yet expand where the other field is limited. Both MRI and behavior represent points of intersection from which in-roads can be planned to understand normal and abnormal development. In my talk, I will present data showing how the study of childhood exposure to adversity can inform and be informed by preclinical studies. The main area of emphasis will be developmental mechanisms of how stress influences behavior and brain anatomy, how parallel findings with MRI in humans and histology in animals can lead to advances in understanding how depression unfolds over the course of maturation. The goal is to find ways that clinical and preclinical researchers may work better together to develop novel strategies aimed not only at symptom reduction, but prevention of a number of psychiatric illnesses. By harnessing the powers of development, it may be possible to reach such a goal.

Plenary Session #3
Brain Research in the Context of Adolescent Development Research: Implications for Prevention Policy Aimed at Reducing High-Risk Behaviors

Friday, June 4, 2010, 10:15 am – 11:45 am
Roundtable follows 1:00 pm – 2:30 pm

Chair: Robert Freeman, NIAAA
Presenters: Robert Zucker, PhD, University of Michigan, Ronald Dahl, PhD, University of Pittsburgh Medical Center, Susan L. Ames, PhD, Claremont Graduate University, School of Community and Global Health

This panel brings together three researchers who have made substantial contributions to understanding how patterns of substance use, risk-taking, and involvement in a range of behavioral and emotional disorders develop during adolescence and emerging adulthood. As these problems contribute to significant mortality morbidity that often extends throughout the lifespan, a deeper understanding as to how and why adolescence creates these vulnerabilities is urgently needed. Such an understanding has the potential to lead to new interventions that can help prevent or postpone hazardous substance use in adolescence and beyond.

Panel presentations will focus on transdisciplinary approaches that illuminate how adolescent vulnerabilities emerge at the interface of biological, behavioral, and social changes during this period of maturation. Robert Zucker describes a conceptual model whereby neurobehavioral changes at puberty lead to increased tendency toward risk-taking, sensation-seeking, and emotional reactivity in adolescence, while the self-regulatory skills and cognitive judgments needed to manage the strong emotional experiences of adolescence tend to mature gradually and relatively slowly across late adolescence. Taken together, these processes result in a maturational gap during which adolescents' behavior tends to be more vulnerable to social influences, and more prone to erratic, risky, and affectively-influenced behavior. Susan Ames describes a dual process model of decision making, cognition, and memory that focuses on a dynamic interplay between a relatively implicit or automatic appetitive system and an executive control/inhibitory system. The synergistic effects of various automatic and control processes has found support in basic research in diverse areas. This talk will include recent imaging and neurocognitive findings in addressing the implications of the developing balance between the subcortical and frontal regions of the adolescent brain. Ronald Dahl describes the contribution of functional magnetic imaging to study brain response in exploring whether patterns of emotional monitoring and affect control differ between vulnerable and resilient late adolescents and young adults. Results suggest that vulnerable youth are less likely to anticipate negative outcomes and more likely to act impulsively, leading to problematic behavior. Panelists will provide specific examples of opportunities for early intervention in high-risk adolescents, as well as discuss the broader implications of transdisciplinary research to advance understanding of the unique opportunities for prevention in adolescence.

Risk and Resilience in Adolescent Children of Alcoholics: How the Brain-Behavior Dialog Informs About Previously Unexpected Relationships
Presenter: Robert A. Zucker, PhD

Resilience is the avoidance of psychopathology, or alternatively the achievement of a successful adaptation despite the experience of adversity that is associated with elevated risk for a symptomatic outcome. Children of alcoholics (COAs), are one such high adversity group; they are at elevated risk for the development of alcohol use disorder by way of the genetic vulnerability their alcoholic familiality conveys, their early and sustained exposure to a heavy drinking subculture, a socialization experience that exposes them to high stress over long periods of time, and permits their early involvement with deviant and heavy drinking peers. Despite these challenges, not all COAs will develop AUD. Critical questions for the field are: what diverts some COAs from exposure to the adversity, or alternatively, what behavioral repertoire allows some of them to overcome it.

Research designs addressing these questions are of two types: one focuses on parsing the behavioral repertoire and environmental contexts that allow resilient behavior to take place. The other focuses on the mechanistic underpinnings of resilience as a strategy for deconstructing the core attributes of a resilient response. This presentation describes work using this second strategy, in particular, the use of functional magnetic imaging (fMRI) to study brain response in a risk related task to address the question. Given that difficulty in restraining affective response is a precursive risk factor for alcoholism, we asked whether patterns of emotional monitoring and affect control differed between vulnerable and resilient late adolescents and young adults. An affect arousal task was used during fMRI acquisition, and patterns of response were compared between the two groups. Both had familial risk (i.e., were family history positive (FH+).), but one group already showed risk vulnerability because they were high in alcohol problems. The other group was not. A third, low risk group was used to control for family risk; it was low in problems and it lacked the positive family history.

Under conditions of emotional arousal, the resilient group showed a response pattern of increased activation in brain regions that involve monitoring and evaluation of emotional state (insula, orbitofrontal cortex), suggesting a greater capacity for active emotional monitoring. In contrast, the vulnerable group did not show increased activation in these areas, but did in sites responsible for control of emotional response (dorsomedial prefrontal cortex) and for the dissociation between sensory and emotional experience. These differences suggest vulnerable youth will be less likely to anticipate negative outcomes, and more likely to act impulsively, leading to inappropriate, problematic behavior.

In the context of the focus of this symposium, the psychological functional differences suggested by the neuroimaging data, although mechanistically very plausible, are not in areas where behavioral research had yet led us. Thus the collaboration has opened up a line of research on possible new foci for preventive work, in an area whose importance had not previously been recognized. Some remarks will also be addressed to the type of research metatstructure necessary for this kind of cross-disciplinary collaboration, and to the considerable rewards of such work.

Supported by grants from NIAAA (R01 AA12217 and R37 AA07065) and NIDA (K01 DA020088 and R01 DA027261) and a NARSAD award.

Transdisciplinary Research on Adolescent Brain Development: A Framework for Understanding Unique Opportunities for Prevention
Presenter: Ronald E Dahl, PhD

Adolescence is a period of increased rates of risk-taking, dangerous behaviors, and for developing a wide range of behavioral and emotional disorders. These problems contribute to significant mortality as well as a great deal of morbidity that begins in adolescence but often extends throughout the lifespan. Thus, there is a compelling need for a deeper understanding as to how and why adolescence creates these vulnerabilities. This presentation focuses on transdisciplinary approaches to understanding how these vulnerabilities emerge at the interface of biological, behavioral, and social changes during this period of maturation—and how these approaches can provide unique insights regarding opportunities for early intervention and prevention. More specifically, a conceptual model is described that focuses on neurobehavioral changes at puberty, which lead to an increased tendency toward risk-taking, sensation-seeking, and emotional reactivity in adolescence. These biologically-based changes in affective neural systems contribute to emotional and motivational changes that typically begin to manifest relatively early in adolescence. In contrast, the self-regulatory skills and cognitive judgments needed to manage the strong emotional experiences of adolescence tend to mature gradually (and relatively slowly) across late adolescence. Taken together—these early affective changes and the slow gradual maturation of cognitive control—can lead to a maturational gap during which adolescents' behavior tends to be more vulnerable to social influences, and more prone to erratic, risky, and affectively-influenced behavior. This presentation will present empirical data from controlled studies that support key aspects of this model, focusing on puberty-specific changes in sleep, emotion, and motivation. In addition, this model will be used to focus on three specific examples of opportunities for early intervention in high-risk adolescents: a) improving emotion regulation skills, b) improving sleep/wake patterns, and c) increasing physical activity. The final part of the presentation will discuss the broader implications and need for more transdisciplinary research to advance understanding of the unique opportunities for prevention in adolescence.

A Neuro-developmental Perspective of Implicit and Control Processes in Appetitive Habit Formation
Presenter: Susan L. Ames, Ph.D.,

Dual process models of decision making, cognition, and memory have gained substantial momentum in basic behavioral and health behavior research. These models describe a dynamic interplay between a relatively implicit or automatic appetitive system and an executive control/inhibitory system. Automatic associative processes reinforced by appetitive behaviors (e.g., alcohol, other drug use, sex) have neurobiological consequences that affect subsequent behavior. As a result of continued substance use, automatic associative processes become increasingly stronger, overriding or overwhelming control processes, with the addictive behavior coming more under stimulus- and less under voluntary control (e.g., Stacy, Ames & Knowlton, 2004). Yet, there are individual and developmental differences in the balance of these systems. Implicitly activated, risky associations may be most readily translated into behavior among those (of all ages) without sufficient protection in executive control functions, such as adequate affective decision making and impulse control. Additionally, since frontal regions supporting protective control functions are not fully developed among youth, the dual process model argues that there will be less of an adaptive counterbalance in reflective and decision ability in youth. Automatic associations promoting appetitive habits like alcohol or drug use are free to develop and strengthen, while control processes are not yet sufficiently adaptive. At the same time, excessive substance use prior to complete prefrontal development may impair subsequent development in important protective functions. This neuro-developmental perspective suggests that adolescents in mid to late teens may be especially susceptible to these risks, which are compounded by the increase in likelihood of heavy alcohol or drug use episodes during these ages. This interaction, underscoring the synergistic effects of various automatic and control processes, has been supported in basic research in diverse areas. This talk will address the plausible developmental relations of these systems, with implications for the developing balance between subcortical and frontal regions, as well as present recent imaging and neurocognitive findings from our lab. Implications for prevention programming will be discussed. Adolescence and emerging adulthood are periods with the highest rates of onset of substance use, leading to likely neural effects and interactions with developmental processes. Understanding these processes may enhance our knowledge of the development of persistent substance use, ultimately leading to new interventions that can help prevent or at least postpone substance use during development and potentially prevent hazardous use in adolescence and beyond.