Ronald E. Dahl, M.D. - US grants

Although EEG sleep changes are an important psychobiologic marker in adult affective disorders, sleep studies of children and adolescents with major depressive disorder (MDD) have revealed conflicting results. In studies of adolescents with MDD, reduced REM latency findings occur in inpatient samples (and in one outpatient study with uniform bedtimes). Two interpretations could account for these findings: 1) They could result from differences in inpatient samples (e.g. severity of illness, comorbidity, or suicidality). 2) These differences could result from some aspect of hospitalization. As will be presented in this proposal, evidence from adolescent sleep studies and from our own findings indicate sleep-wake schedules and/or adaptation effects are likely to be central to these findings. The purpose of this study is to substantiate this interpretation and to test two complimentary hypotheses: I) With precise control of sleep times and schedules in all subjects, reduced REM latency will be detected in both inpatient and outpatient MDD groups compared to normal adolescent controls. II) REM latency will e reduced further in MDD adolescents in response to transient sleep restriction (as often occurs during hospitalization). The following protocols will be utilized to test these hypotheses. Outpatient Protocol: Outpatient MDD adolescents and normal adolescent controls will follow a precise schedule for one week corresponding to the inpatient schedule monitored by activity meters, sleep log, and telephone verification. In the second week, three nights of sleep restriction, then two nights of recovery sleep. Inpatient Protocol: Inpatient adolescents with MDD will undergo five consecutive nights of EEg sleep recording (during the first week of admission) while adapting to the impatient unit. In the second week, they will follow the same schedule of baseline, partial sleep deprivation, and recovery sleep recording in the sleep lab as in the outpatient protocol. Data analyses will compare sleep measures between groups (inpatients, outpatients and controls) for each condition (baseline and recovery). Additional analyses will compare sleep variables across conditions of baseline and recovery sleep within each group. Within the inpatient group, analyses will also examine night to night changes during the transition period to the ward. This study addresses a central issue in the psychobiology of adolescent affective disorders. Delineating the roles of erratic sleep schedules, transient sleep restriction, and adaptation effects, is crucial to our understanding of sleep changes in adolescent MDD.

DESCRIPTION (Adapted from applicant's abstract): This K02 application out-lines research and career development plans to investigate the role of sleep regulation in the developmental psychobiology of affective disorders. The first goal is to extend a well-established line of research based on measures of EEG sleep and cortisol in child and adolescent depression by investigating: (1) abnormalities in sleep and cortisol regulation focusing on the sleep-onset transition; (2) normal maturational changes in sleep and cortisol regulation relevant to these abnormalities; and (3) the predictive validity of sleep and cortisol abnormalities in longitudinal clinical follow-up. The second goal is to further develop and investigate a larger developmental model of sleep regulation. The model emphasizes close links between sleep regulation and neurobehavioral systems involved in the regulation of affect and arousal which are modulated in regions of prefrontal cortex (PFC). Matur-ational changes in PFC-subcortical circuits influencing sleep, arousal, and affect are hypothesized to contribute to sleep changes associated with depression, particularly near the transition from wakefulness into sleep. Based on this model, predictions are made regarding sleep changes in the development of affective disorders and effects of sleep deprivation of affective regulation. The long-term goal of this work is to understand mechanisms of dysregulation which may lead to more effective treatment of early onset affective disorders. Career development activities to support these goals are described. Further advancing this line of investigation will require increased knowledge and skills in four areas: the development of affect regulation; the relevant neurocircuitry and its development; more direct measures of the neural systems of interest; and statistics. The candidate will pursue these goals through course work, focused readings, and supervised learning experiences and collab-orations with scientists locally and nationally.

anxiety disorders; depression; psychobiology; neuroendocrine system; neuroanatomy; child psychology; dopamine agonists; sleep; clonidine; 5 hydroxytryptophan; child mental disorders; corticotropin releasing factor; hypothalamic pituitary axis; growth hormone releasing hormone; social psychology; behavioral /social science research tag; clinical research; middle childhood (6-11); electroencephalography; human subject;

behavioral /social science research tag; fluorimetry

The program of research described in this application uses measures of sleep, arousal, pubertal timing, and family history of alcohol dependence to examine developmental trajectories from childhood affective disorders to adolescent alcohol problems. It is hypothesized that an altered pattern of sleep/arousal regulation in children with anxiety and affective disorders will predict elevated rates of alcohol abuse/dependence during clinical follow-up across late-adolescence and into early adulthood. This work builds upon an existing psychobiologic study where a broad range of biological, clinical, and family history data have been obtained in samples of children with depression, anxiety disorders, controls with high family loading for affective disorders, and low-risk controls. The investigations described in the current proposal will add a new set of measures and analyses to that existing study, in order to address key questions relevant to adolescent development, sleep and arousal regulation, and pathways to alcohol abuse/dependence into early adulthood. These new measures will include multi variate EEG analyses applied to previously collected sleep data. Subjects (n=367) had psychobiologic measures obtained at ages 8-14 years of age and will be followed longitudinally for alcohol use problems developing across adolescence. The study will also examine gender differences and the influence of early pubertal timing on the development of affective and alcohol disorders. The study will obtain new biologic data on an informative sub-sample of subjects (n=90) studied in later pubertal maturation (ages 14-21). The long-term goal of this research is to understand maturational changes in sleep, arousal, and affect regulation across adolescence relevant to the development of alcohol abuse and dependence. Advancing knowledge in these areas may lead to more effective early intervention strategies (prevention or early treatment) for alcohol abuse/dependence in targeted high-risk populations of youth.

DESCRIPTION: (provided by applicant) Neuroimaging studies of mid-life major depressive disorder (MDD), have revealed abnormalities of cerebral function and structure that persist beyond depressive episodes. To test hypotheses about the neurobiological basis of MDD, the systems implicated by these studies will be examined in a unique and informative sample of young adults: Subjects now age 18 to 24 previously identified in childhood as having MDD or as being at 'high risk' (HR) for developing MDD by virtue of having multiple affected relatives. These samples will be compared against healthy, low-risk' (LR) controls (who have no evidence of having first or second degree relatives with mood disorders) with respect to PET and MRI imaging measures of neurophysiology, serotoninlA receptor binding potential (BP), and neuromorphometry that proved abnormal in both the symptomatic and asymptomatic phases of mid-life MDD). Since these abnormalities involve brain structures implicated in emotional behavior by lesion analysis, electrophysiological orPET/fMRI-brain mapping studies, they appear likely to be relevant to the pathogenesis of mood disorders. It remains unclear, however, whether such abnormalities reflect developmental or acquired processes that predate the onset of depressive episodes, or whether they instead comprise sequelae of recurrent illness or treatment in MDD. The proposed project addresses this question by bringing these measures closer to the developmental period in young adults with childhood-onset MDD and by assessing their existence in subjects at high risk for MDD. Three samples will be selected: childhood-onset MDD subjects who are unmedicated and in remission, HR subjects who are psychiatrically healthy, and LR healthy controls. PET measures of serotoninlA (5-HTIA) receptor binding and glucose metabolism will be acquired using serial injection of the 5-HTJA receptor ligand, jcarbonyl-11C] WAY-100635, and 18F-fluorodeoxyglucose. MRI-based neuromorphometric assessments of the subgenual prefrontal cortex (PFC; where reduced grey matter was found in both in vivo MRI and post mortem neuropathological studies of MDD) will also be performed. We will test the hypotheses that, relative to the LR control group, both the MDD and the HR groups will have reduced 5-HT1A receptor BP in the mesiotemporal cortex and the raphe, decreased left subgenual PFC volume, increased left amygdala metabolism, and decreased dorsomedial/dorsal anterolateral PFC metabolism. In post hoc comparisons, the relationship between the PET data and plasma and salivary cortisol levels will be assessed to test the hypotheses that 5-HT1A receptor binding down-regulation in MDD is related to elevated cortisol exposure, and to explore whether HR subjects with past evidence of HPA-axis dysregulation have reduced 5-HT1A receptor BP.

This Independent Scientist Award (K02) renewal application describes career development activities and a program of research focusing on links between sleep, arousal, and affect regulation. The conceptual framework emphasizes a developmental perspective and clinically relevant hypotheses regarding pathways to adolescent depression. This application outlines four new or modified aims to the previous work: 1) To sharpen the developmental focus to the period of early adolescence/onset of puberty as a time of brain maturation with particular relevance to the development of affect regulation (and affective disorders). 2) To strengthen the cognitive-neuroscience approach to understanding affect regulation and depression in adolescence (including methodological and conceptual advances in the use of neuroimaging studies). 3) To expand the clinical outcomes of interest to include adolescent alcohol and nicotine use. 4) To use experience-sampling methodologies to obtain ecologically valid assessments (EMA) of mood, behavior, and sleep patterns in adolescents' home environments. The research plans to carry out these aims include ongoing and planned studies in pert-pubertal subjects to investigate early adolescent brain maturation and functional brain changes associated with depression. The research also includes longitudinal clinical follow-up studies of subjects (samples of normal controls, high-risk, anxious, and depressed children) who previously underwent comprehensive psychobiologic and maturational assessments. These samples are being followed through late adolescence and into early adulthood to examine developmental pathways to depression, nicotine, and alcohol use. This research (along with the linked career development activities) will lead to a better understanding of brain maturation in early adolescence and the development of affect regulation. The long-term goals are to inform early interventions to help prevent the development of adolescent-onset affective disorders and substance dependence.

[unreadable] DESCRIPTION (provided by applicant): This application describes a Research Network aimed at conceptual and methodological advances in understanding affect dysregulation in adolescence. The central theme for this project is the development and refinement of measures of affect regulation that can be used to investigate neurobehavioral systems in adolescents within a developmental framework. These include tasks that can be used in functional MRI and ERP (event-related potential) studies to examine the development of neurobehavioral systems in both clinical and normative populations of adolescents. It is also important to devise experimental paradigms that address clinically relevant and ecologically valid aspects of emotion and its regulation. This will require developing better conceptual models and formulating specific hypotheses about affective changes in developmental pathways of emotional disorders in adolescence. The long-term goals of this work are to address clinically relevant questions-to identify developmental pathways and mechanisms of affect dysregulation that can inform treatment strategies for early-onset depression, anxiety, and other emotional disorders emerging in adolescence. We focus on adolescence because this developmental phase represents a period of increased vulnerabilities for emotional disorders, yet also presents opportunities for early intervention. Ultimately, mechanistic understanding of the development of affect regulation can lead to prevention strategies targeting high-risk populations prior to the onset of more serious emotional disorders. A deeper understanding of affect regulation in adolescence may also provide insights into behaviors such as increased sensation seeking, risk-taking, and substance use-common behaviors in adolescence that can lead to serious consequences. The specific aims of this research network are: (1) To develop and refine fMRI and ERP tasks of emotion regulation that can be used in clinical and developmental studies of older children and adolescents. (2) To develop and refine behavioral and experience-sampling methods of assessing emotion and its regulation in the natural environments of adolescents. (3) To improve heuristic models of affect regulation and dysregulation during adolescent development within a cognitive/affective neuroscience framework. (4) To provide outstanding interdisciplinary training experiences for young investigators. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The New York Academy of Sciences is sponsoring a 2.5 day conference titled "Adolescent Brain Development: Vulnerabilities and Opportunities," scheduled for September 18-20, 2003, in New York City. Adolescent development involves complex changes in neurobehavioral systems underpinning the control of emotion and behavior; this period is often difficult and accompanied with steep rise in mortality and morbidity related to the control of behavior and emotions, some of which have significant long-term consequences. A multitude of biological, psychological, and social changes occur rapidly during this interval and a developmental framework is essential to examine questions about specific maturational processes-including pubertal brain and body changes-and the unique opportunities and vulnerabilities created by these developmental processes. Establishing a better understanding of these processes can help inform the timing and focus of interventions (and eventually preventive efforts) to shift the trajectories away from negative outcomes, and toward healthy positive pathways. A critical problem in this area is the dearth of basic knowledge about human brain development during puberty and adolescence-particularly the maturation of neurobehavioral systems involved in affect regulation and behavioral choices that have enormous clinical and social policy relevance. However, significant progress has recently been made in a number of areas relevant to these issues. There is a critical need at this time for better integration across the variety of areas where rapid progress is being made with a specific focus on the neurobehavioral changes during normal adolescent development that contribute to increased risk-taking and/or reward seeking. The purpose of this conference is to bring together basic and clinical investigators from a number of different areas to begin a better-integrated dialogue to move the field forward. Discussion during the conference will include studies in animal models that can inform key aspects of human brain development and the usefulness of new tools (such as functional neuroimaging and genetic studies). The long-term goal is to stimulate further interdisciplinary research and advance understanding with clinical and policy relevance to a wide range of adolescent-onset health problems-particularly the development of nicotine dependence, alcohol and other substance use, risk-taking behaviors, depression and suicide.

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 application describes a developmental study of emotion, motivation, and decision-making in adolescence. The study focuses on the neural basis for affective changes during pubertal maturation, with an emphasis on sensation-seeking, reward-seeking, and risk-taking relevant to understanding adolescent vulnerability to substance use disorders. The design is aimed at disentangling puberty-dependent versus puberty-independent aspects of adolescent behavioral and brain development. This will be accomplished by comparing samples matched on age but differing in pubertal maturation and then re-studying each sample after two years of additional development. Measures at each time point will include: structural and functional imaging of neural systems mediating affective behaviors;behavioral measures of decision-making and inhibitory control;and experience-sampling measures of adolescents'mood, motivation, and reward-seeking behavior in their natural home environments. In addition, the study will examine the influence of heritable variation in monoamine function (dopamine and serotonin) on the development of these neural systems and affective behaviors. Through the convergence of these methodologies, this study aims at understanding maturational shifts in the functional relationships between limbic and prefrontal brain regions that may contribute to a transient increase in the tendency toward risky behavior and cause these behaviors to be experienced as more rewarding in adolescence--particularly in some individuals and in some social contexts. The short-term goals of this work are to test hypotheses about puberty-specific changes in affective brain systems that influence decision-making in adolescents and key sources of individual differences during this developmental period. The long-term goals of this work are to identify developmental pathways and biological mechanisms of vulnerability toward substance use disorders in ways that will inform early intervention and prevention strategies.

DESCRIPTION (provided by applicant): Mental and behavioral health during adolescence is an area of critical public health concern because morbidity and mortality rates increase 200-300% from childhood to late adolescence. A major dimension of these serious health problems is related to difficulties with the control of emotions. In order to understand how challenges to emotion regulation during adolescence contribute to specific health problems, researchers need better tools for measuring emotional reactivity and regulation during this developmental period. This project applies a developmentally informed social affective neuroscience perspective to the development of a new "toolbox" for studying emotional reactivity and regulation in adolescence. This requires an integration of the fields of developmental psychopathology, social neuroscience, and affective neuroscience. Combining key elements of these disciplines will facilitate the development of tools grounded in neuroscience that also have broader developmental, clinical, and social relevance. Because of the importance of the social sphere in adolescence, we focus on socially relevant paradigms that will facilitate an understanding of how social influences (e.g. parents, peers, media) contribute to adolescents'emotionality, and how neurobiological substrates underlie social and emotional processes. Specifically, we will develop and refine 3 sets of tools: (a) laboratory pupillary and functional magnetic resonance imaging (fMRI) social-emotional information processing tasks;(b) behavioral observation of parent-child affective interactions with concurrent pupillary data;and (c) a cell-phone based Ecological Momentary Assessment (EMA) protocol measuring adolescents'emotional reactivity and regulation in natural social contexts. Our aims are to (1) develop and establish initial psychometric properties for these measures, (2) integrate these measurement approaches across levels of context and time, and (3) examine the validity of these approaches in discriminating clinical groups and detecting developmental/pubertal differences in emotional reactivity and regulation. As first steps, we will focus specifically on the utility of these methods in research on adolescent depression--a common and debilitating adolescent health problem associated with chronic and recurrent impairment into adulthood. Innovative aspects of this work include the development of new methodologies for sampling "real-world" phenomena, integration of neuroscience with the social environment by developing laboratory paradigms that tap social processes, and improvements in the assessment of co-occurring social and biological processes through the development of mood inductions and peer and parent-child interaction tasks that can be used to collect concurrent neurobiological, behavioral and observational data. Ultimately, these tools could be useful for investigators examining a wide range of adolescent health problems across disciplines, including researchers in the areas of high risk research, treatment and prevention, longitudinal developmental research, psychology, neuroscience, and behavioral medicine. Developing new biological and ecological tools for measuring emotional reactivity and regulation is relevant to the missions of NICHD, NIMH, NIDA, and NIAAA in that emotion regulation has been identified as a critical yet poorly understood domain in normative child and adolescent development and in the development of problems in mental health, drug and alcohol abuse, and risk-taking and reckless behavior that leads to a broad range of health consequences. Developing tools that can facilitate a better understanding of the mechanisms through which emotional reactivity and regulation contribute to adolescent health is critical because it could lead to improvements or adaptations of existing prevention and intervention programs, the development of new prevention and intervention programs based on new scientific discoveries, and better matching of patients to specific treatment protocols based on emotional profiles. Tools that can identify initial disruptions in emotion regulation and facilitate early intervention during this period of relative plasticity could lead to long-term reductions in health-related cost and suffering in adulthood.

0-11 years old; 12-20 years old; AOD use; Accidents; Active Follow-up; Address; Adolescence; Affect; Affective; Affective Disorders; Affective Psychosis, Bipolar; Age; Alcohol or Other Drugs use; Alcohols; Anxiety; Anxiety Disorders; Behavioral; Bipolar Disorder; Cats; Chemical Class, Alcohol; Child; Child Youth; Children (0-21); Chronic Insomnia; Circadian Rhythms; Clinical; Clinical assessments; Cognitive; Depression; Development; Distress; Diurnal Rhythm; Domestic Cats; Dysthymic Disorder; Early Intervention; Early Intervention (Education); Effects, Longterm; Emotional; Feline Species; Felis catus; Felis domestica; Felis domesticus; Felis sylvestris catus; Generalized Anxiety Disorder; Goals; Health; Home; Home environment; Human, Child; Insomnia, Chronic; Intervention; Intervention Strategies; Laboratories; Lead; Long-Term Effects; Mammals, Cats; Measures; Mediating; Mental Depression; Metabolic syndrome; Mood Disorders; Moods; Nicotine; Nyctohemeral Rhythm; Obesity; Outcome; Outcome Measure; Pb element; Prevention strategy; Preventive strategy; Protocols, Treatment; Psychosis, Manic-Depressive; Puberty; Public Health; Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-; RGM; Randomized; Range; Rate; Regimen; Regulation; Risk; Risk Factors; Role; SCHED; Schedule; Sleep; Sleep Disorders; Sleep disturbances; Social Functioning; Social Policies; Stress; Substance Use Disorder; Symptoms; System; System, LOINC Axis 4; Testing; Time; Treatment Protocols; Treatment Regimen; Treatment Schedule; Twenty-Four Hour Rhythm; Week; Youth; Youth 10-21; actigraphy; adiposity; adolescence (12-20); behavior observation; behavioral observation; bipolar affective disorder; children; circadian; circadian process; clinical relevance; clinically relevant; coping; corpulence; corpulency; corpulentia; daily biorhythm; day; diurnal variation; dysthymia; emotion regulation; follow-up; heavy metal Pb; heavy metal lead; human puberty; improved; interventional strategy; manic depressive disorder; manic depressive illness; obese; obese people; obese person; obese population; protective effect; public health medicine (field); randomisation; randomization; randomly assigned; sleep problem; social role; substance use; teenage; vigilance; youngster

DESCRIPTION (provided by applicant): The primary goal of this project is to examine the short and long-term effects of a preventive intervention focusing on three interrelated dimensions of health: improving sleep, increasing physical activity, and improving skills in emotion regulation. This intervention targets high-risk youth at a key neuromaturational period-early adolescence-when many individuals are experiencing new challenges to regulatory systems involved in sleep, activity, and emotion regulation. This maturational period is also a crucial time in the normal development of habits, skills, and proclivities in each of these domains. Thus, early adolescence presents unique opportunities for a preventive intervention targeting these three interrelated regulatory systems. Participants will include 160 10-13 year-old children whose families are identified on the basis of sociodemographic, child, and/or family risk. Children will be selected as having difficulties in at least one of these domains (sleep, sedentary behavior, or emotion regulation) and then randomly assigned to either a control or intervention group. All families will receive baseline, one- and two-year follow-up assessments of child sleep, physical activity, and emotion regulation. Families in the preventive intervention group will be offered feedback and intervention services on these three child domains and other parenting and family issues (e.g., parent involvement, parent self-care, school problems) following the initial assessment and the one-year follow up. We hypothesize that the intervention will be associated with improvements in sleep, physical activity, and emotion regulation among those in the intervention group, as well as improvements in measures of social, behavioral, and affective function. Finally, we will explore the possibility that increases in parental involvement mediate some of the changes found in child sleep, physical activity, and emotion regulation. PUBLIC HEALTH RELEVANCE: This project addresses a set of issues with enormous relevance to public health and policy, targeting early intervention to improve sleep, physical activity, and affect regulation, at a sensitive period in development. Evidence supporting the effectiveness of these interventions, and demonstrating enduring effects from the optimal developmental timing of the intervention in early adolescence would have major public health implications relevant to a broad range of behavioral, emotional, and physical health outcomes.

This Science of Learning Collaborative Network brings together researchers from across the University of California-Berkeley and the University of California-San Francisco, to advance scientific understanding of developmental changes that occur in the learning processes of children and adolescents. Growing evidence shows that learning processes and the underlying brain systems go through important developmental changes. These changes begin during infancy and early childhood, but they also extend much later in pubertal maturation and adolescent development. A team-science approach will be used to address these complex issues. The collaborative research network includes expertise in the developmental science of adolescence, and in the science of learning in both human and animal models. A deeper understanding of the developmental changes in specific learning processes in adolescence will inform educational methods and interventions. With greater developmental precision, it should be possible to design more effective education for specific age groups. The long-term goals are to help transform the adolescent "window of vulnerability" (when so many youth become bored and disengaged from school) into a "window of opportunity" (a natural period of curiosity, exploration, and unique learning opportunities).

This collaborative research network builds upon (and helps to integrate) four distinct areas in the science of learning: a) the developmental science of adolescence; b) animal models of brain development in adolescence; c) animal models of learning, and d) computational modeling of learning in humans and animals. The network members will work together to develop new methods, tasks, and analyses that better isolate specific learning variables under transition at adolescence. By tracking pubertal measures as well as age, the work is expected to illuminate the role of puberty onset in developmental transitions in learning, independent from age. The use of mouse models will enable experiments that delineate the role of specific aspects (and timing) of puberty in relation to these specific changes in learning. The integration of human and animal models in parallel experiments will establish a bridge between the fields of developmental science, computational neuroscience, cognitive neuroscience, and systems neurobiology. Scientists and trainees will participate in 'cross-training' opportunities through network meetings, contributing to building a stronger interdisciplinary culture of interaction and collaboration. Undergraduate trainees from underserved backgrounds will also participate in the network.

The award is from the Science of Learning-Collaborative Networks (SL-CN) Program, with funding from the SBE Division of Behavioral and Cognitive Sciences (BCS), the SBE Office of Multidisciplinary Activities (SMA), and the CISE Division of Computer and Network Systems (CNS).