Ian H. Gotlib - US grants

Depression is among the most prevalent of all psychiatric disorders, accounting for over 20 percent of economic costs for all mental illness. A great deal of theoretical attention has focused on the possibility that negative thinking might represent not only a feature of depression, but a vulnerability factor for this disorder as well. A recent influential research paradigm has operationalized depressotypic cognitions in terms of selective attention to, and memory for, negative emotional stimuli. The overall goal of the proposed investigations is to utilize this paradigm to investigate the role of cognitive biases in onset and course of depression, and to examine neurobiological foundations of cognitive biases in depression. Specific aims include (1) examining the utility of cognitive biases to predict the course of depressive symptoms and diagnostic status over a two-year period; (2) localizing the neurobiological underpinnings of these biases; and (3) examining the breadth of these biases and their specificity to depression. To achieve these aims, standardized cognitive information- processing tasks will be used to identify 30 "high-bias" and 30 "low- bias" depressed patients in psychiatric outpatient clinics. The nature and breadth of these biases in the depressed patients will be compared to cognitive biases among 30 patients diagnoses with generalized anxiety disorder, 30 patients diagnosed with social phobia, and 30 non-patient controls. Each depressed patient will be followed for one year, and the degree of cognitive biases will be reassessed when the patient achieves clinical remission. Hypotheses concerning the neurobiological underpinnings of depressotypic cognitive biases will be tested by conducting functional magnetic resonance imaging (MRI) of depressed (and later, remitted) patients while they are performing information- processing tasks.

DESCRIPTION (Applicant's Abstract): This program provides training for careers in basic research in personality, emotion, and psychopathology. It emphasizes basic theory and psychological mechanisms, training in experimental methodologies, and broad integrative approaches to personality, emotion, and emotion regulation. Trainees will be predoctoral students working towards a Ph.D. in psychology. The curriculum includes a solid foundation in core courses and advanced seminars dealing with basic psychological mechanisms, supplemented by specialized seminars that examine promising new theoretical and methodological advances in psychology. In consultation with faculty, students plan an individualized program of elective courses to acquire skills and background relevant to their specific research interests. The training program generally requires four years beyond the Bachelor's degree, and follows the requirements of the Psychology Department. Students begin their intensive training in research by means of a tutorial system in which each student collaborates closely with a particular faculty member. As they proceed through the program, students take increasing responsibility for originating and conducting research studies. The research conducted by students and faculty focuses generally on basic psychological mechanisms governing individual differences in emotion, emotion regulation, and behavior in diverse samples of children, adolescents, and adults. Specific research foci of the core faculty in the program include the role of self-efficacy in the regulation of affective states, health, and illness; processes by which people adapt their emotion-regulation strategies to the faced at different points in the life-span; the role of interpersonal styles in emotion regulation; psychosocial factors in depression; mechanisms underlying the intergenerational transmission of risk for psychopathology; and the physiological, behavioral, and affective consequences of emotion suppression. The populations studied range from normal and disordered children, to adolescents and their parents in the community, to adult psychiatric patients, to patients at risk for cardiovascular disease, to the very old. Students have access to numerous research settings, both on the Stanford campus and in the surrounding community. Funds are requested to support five (5) predoctoral trainees per year.

DESCRIPTION (provided by applicant): Depression is among the most prevalent of all psychiatric disorders, accounting for over 20% of economic costs for all mental illness. An important public health priority is the development of methods for identifying factors that both increase individuals' vulnerability to depression and hinder recovery from this disorder. Pursuing this objective, we have been conducting research that broadens the focus of cognitive models of depression by examining patterns of biological reactivity to emotional stimuli. Extrapolating from our earlier studies and from existing models, we predicted that individuals diagnosed with Major Depressive Disorder (MDD) would exhibit increased autonomic arousal and neural activation in response to negative stimuli. But our findings indicated otherwise; in both fMRI and psychophysiological studies, MDD individuals demonstrated less activation and arousal in response to both positive and negative stimuli than did nondepressed controls. Moreover, greater activation and reactivity predicted improved functioning over the following year, independent of MDD severity. In reconciling and integrating these results with our earlier findings, we are broadening and refining cognitive theories of depression to include a consideration of affective chronometry, sensitivity to reward stimuli, and biological functioning, not only to describe the functioning of depressed individuals, but also to predict recovery from this disorder. The studies proposed in this application are designed to test a more comprehensive formulation of depression and to systematically rule out important alternative explanations for our obtained results. Based on our initial findings, we posit that when confronted with an emotionally-valenced stimulus, depressed persons immediately attend to it; if the stimulus persists, they shut down their processing and disengage from it. Moreover, those depressed individuals who are able to stay engaged with emotional stimuli are likely to recover from depression most quickly. The overall objective of this proposed project is to advance our understanding of the cognitive and neurobiological responses in MDD to emotional stimuli. We are particularly interested in the effects of stimulus type (i.e., affective valence), stimulus duration (i.e., affective chronometry), and the potential effects of specific patient characteristics (e.g., anhedonia, comorbid Axis-II personality disorder) on emotional functioning in depression. We propose to examine information-processing biases and reward responsivity, as well as concomitant neural activation and psychophysiological arousal, in response to emotional stimuli in depressed and nondepressed participants. Findings from the proposed studies testing these formulations will contribute importantly to the development of an integrative psychobiological theory of depression.

DESCRIPTION (provided by applicant): The Psychopathology and Affective Science (PAS) program in the Department of Psychology at Stanford University provides training for careers ranging from basic research in affective processes and neuroscience to applied research in psychopathology. It emphasizes the experimental study of psychological and psychobiological mechanisms; theory development, and applications to problems of mental health and disorder. The psychology department at Stanford has a long history of training researchers with expertise in basic psychological processes studied within the context of real-world problems. We believe that the best research focuses on core psychological and psychobiological mechanisms, and that progress is most rapid when mechanisms are understood in the context of improving mental health. Trainees are pre-doctoral students working towards a Ph.D., and postdoctoral fellows seeking advanced training in psychopathology and affective science. Funds are requested to support four pre-doctoral and two postdoctoral trainees per year. The training curriculum includes a solid foundation in core courses and advanced seminars dealing with basic and applied psychological mechanisms, supplemented by specialized seminars that examine new theoretical and methodological advances. Emphasis is placed on research methods and the integration of divergent theories and methods to elucidate problems of interest. Trainees begin their intensive training in research by means of a tutorial system in which each trainee collaborates closely with a particular faculty member. As they proceed through the program, graduate student trainees take increasing responsibility for originating and conducting research studies, and plan an individualized program of elective courses to acquire skills and background relevant to their specific research interests. Postdoctoral fellows have access to the full array of training opportunities throughout Stanford, and work closely with designated faculty mentors to establish a tailored research and training program.

DESCRIPTION (provided by applicant): Depression is among the most prevalent and costly of all psychiatric disorders. A pressing public health need is to identify factors that play a role in increasing individuals'vulnerability to depression. Offspring of parents with depression are at heightened risk for the development of this disorder. Consequently, assessing these children is of critical importance in elucidating factors and mechanisms associated with this risk. The proposed integrative project is designed to examine biological, cognitive, and psychosocial factors and mechanisms that may elevate the risk for psychopathology in never-disordered 11 - to14-year-old daughters of mothers with a history of recurrent Major Depressive Disorder. We will compare the functioning of this group of girls with that of daughters in two additional age-matched groups: formerly depressed daughters of recurrent depressed mothers, and never-disordered daughters of mothers with no history of psychopathology. We propose to assess two broad constructs that are of critical importance in understanding the increased risk for psychopathology of daughters of depressed mothers: (1) the daughters'perception and evaluation of stressors in their environment, which determine their immediate response to the stressors;and (2) the daughters'regulatory skills in response to the stressors, which determine the long-term consequences of exposure to the stressors. Our study is unique in combining brain imaging techniques, measurement of both diurnal and reactive cortisol levels, assessment of information-processing biases, and self-report measures to assess emotion dysregulation and stress reactivity in daughters of depressed mothers. Working from a diathesis-stress perspective, we will administer stress- and mood-induction procedures prior to assessing the constructs of interest. We will also conduct an 18-month follow-up assessment to examine whether difficulties in stress reactivity and emotion regulation assessed in a nondepressed state predict the onset and/or the recurrence of depressive episodes. These data promise to help us gain a more comprehensive understanding of the interplay of stress reactivity, neuroendocrine functioning, emotion regulation, cognitive processes, and patterns of neural reactivity in placing children of depressed mothers at elevated risk for affective disorder, and will identify critical areas of dysfunction that may serve as targets for prevention programs.

[unreadable] DESCRIPTION (provided by applicant): Depression is among the most prevalent of all psychiatric disorders. It is critical, therefore, that we identify factors involved in the maintenance of depression and factors that impede recovery from this disorder. In a series of behavioral investigations we found depressed individuals to demonstrate biased attentional processing of negative stimuli only in response to prolonged stimulus exposure durations that permit elaboration of the material. Although we also found depressed individuals to exhibit impaired processing of positive stimuli, we demonstrated consistently that greater physiological reactivity and neural activation in response to positive stimuli predicts improved functioning of depressed individuals over the following year. Working to integrate these results has led us to both broaden and refine cognitive theories of depression to include a consideration of the roles of: (a) failure to disengage from negative stimuli; (b) inhibitory dysfunction affecting working memory; (c) long-term memory for emotional material; (d) responsivity to positive stimuli; and (e) patterns of neural activation in response to emotional stimuli and in the regulation of negative affect. In focusing on these constructs, we are gaining a more comprehensive understanding of precisely how cognitive and biological dysfunction can lead to emotional dysregulation and sustained negative affect, hallmark symptoms of depression. We propose a series of studies designed to test an integrative formulation of depression in which we posit different roles for the processing of negative and positive stimuli. We propose that depressed persons experience difficulty disengaging from, and inhibiting elaborative processing of, negative stimuli. We posit further that this inhibitory difficulty increases the likelihood of rumination, which in turn, leads to sustained negative affect. In addition, the attenuated processing by depressed individuals of positive stimuli impairs their ability to use positive memories or information to repair these negative affective states. Indeed, we posit that those depressed individuals who are able to engage most strongly with positive stimuli will recover from depression most quickly. Finally, we propose a series of investigations designed to elucidate the patterns of neural activation that are associated with each of these processes. Findings from these studies will represent important contributions to the continued development of an integrative psychobiological theory of depression. [unreadable] [unreadable] [unreadable]

CRISP; Computer Retrieval of Information on Scientific Projects Database; Data; Depressed mood; Depression; Emotional Depression; Exhibits; Funding; Grant; Individual; Inferior Frontal Convolution; Inferior frontal gyrus; Institution; Investigators; Maintenance; Maintenances; Major Depressive Disorder; Manuals; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Mental Depression; Methods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous; Participant; Play; Process; Recurrence; Recurrent; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Role; Scanning; Short-Term Memory; Source; Symptoms of depression; Thinking; Thinking, function; United States National Institutes of Health; Work; cognitive control; depressed; depressive; depressive symptoms; design; designing; experience; major depression; neural; relating to nervous system; sadness; social role; working memory

DESCRIPTION (provided by applicant): Depression and anxiety are among the most prevalent of all psychiatric disorders. In recent years it has become increasingly apparent that depression and anxiety are highly comorbid. The comorbidity of Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) is particularly pernicious: compared to non-comorbid individuals, persons with this pattern of comorbidity report higher levels of suffering, greater severity of avoidance behavior, greater impairment in social and occupational functioning, and higher risk of suicide. Despite the high co-occurrence of MDD and SAD, few studies have examined the nature of this comorbidity. We do not know, for example, how comorbid patients differ from their diagnostically purer, or non-comorbid, counterparts. It is also unclear whether relapse rates differ for comorbid and non-comorbid patients, or whether the factors that have been found to predict the course of anxiety and depressive disorders are also relevant for understanding their comorbidity. And most important for the purposes of this proposal, we know little about the genetics, or the psychological and biological dysfunctions that are associated with comorbidity. The constructs of stress reactivity, stress recovery, and emotion dysregulation all have been implicated, albeit separately, in understanding the nature of MDD and SAD;we postulate that these constructs are critical in also understanding the comorbidity of these disorders. Thus, in this project we propose to examine and integrate self-report measures, cognitive measures, indicators of hypothalamic-pituitary-adrenal axis functioning, neural responses to emotional stimuli and emotion regulation, and a genetic polymorphism in participants diagnosed with non-comorbid MDD, with non-comorbid SAD, with comorbid MDD/SAD, and with no history of psychiatric disorder. More specifically, we propose to examine in a single project with carefully diagnosed comorbid and non-comorbid participants the roles of: (a) orienting towards and disengaging from negative stimuli;(b) neuroendocrine responses to and recovery from a psychological stressor;(c) patterns of neural activation in response to emotional stimuli;(d) responsivity to, and utilization of, positive material to regulate negative affect;and (e) allele polymorphism on the serotonin transporter gene. Findings from this project will represent important contributions to the development of an integrative psychobiological theory of the comorbidity of depression and anxiety, and promise to elucidate the interplay of stress reactivity, neuroendocrine functioning, emotion regulation, cognitive processes, genetics, and patterns of neural reactivity in comorbid MDD and SAD, and to identify critical areas of dysfunction as targets for intervention programs for this debilitating condition. PUBLIC HEALTH RELEVANCE: Depression and anxiety are among the most prevalent of all psychiatric disorders. In recent years it has become increasingly apparent both that depression and anxiety are highly comorbid, and that this comorbidity is associated with significant adverse outcomes, including a high risk of suicide. This project is proposed to examine the interplay of stress reactivity, neuroendocrine functioning, emotion regulation, cognitive processes, and patterns of brain function in comorbid depression and anxiety. Findings from this project promise to identify critical areas of dysfunction as targets for intervention programs for this debilitating condition.

DESCRIPTION (provided by applicant): Depression is among the most prevalent of all psychiatric disorders. Consistent with the NIH objectives of promoting discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders and charting mental illness trajectories to determine when, where, and how to intervene, a critical public health priority is the development of methods for identifying and altering factors and mechanisms that increase individuals' vulnerability to depression. Offspring of depressed parents are known to be at elevated risk for developing depression; consequently, assessing these children has been an important strategy for elucidating factors associated with the increased risk for psychiatric disorder. To date, however, few studies have gone beyond documenting the magnitude of this risk to examine specific mechanisms that might underlie the intergenerational transmission of risk for depression. Over the last four years we have worked hard to recruit and test a large, carefully diagnosed, sample of 10- to 14-year-old never-disordered girls at either high or low familial risk for depression. Each girl has a biological mother who either has experienced recurrent episodes of Major Depressive Disorder (MDD) during her daughter's lifetime (high risk) or has never experienced an episode of any Axis-I disorder (low risk). Although the high-risk girls are asymptomatic, we have found that they nevertheless already exhibit characteristics of MDD, including selective attention to sad faces, higher and more prolonged cortisol secretion in response to a laboratory stressor, higher levels of awakening cortisol, smaller hippocampi, and anomalous neural functioning both in response to reward and punishment and while experiencing and regulating a sad mood. Because we began recruiting the girls in this study at this young age only four years ago, we have not yet been able to examine fully whether these difficulties predict the subsequent onset of a first episode of MDD. Therefore, we propose to conduct a 54-month follow-up diagnostic session with this sample and to add a second fMRI scan to assess differences in the stability of neural structure and function between high-risk girls who do, and who do not, develop MDD. We also propose to recruit a new sample of high-risk daughters, to teach them either through attentional bias training or through real-time neurofeedback training to alter mechanisms that we posit underlie the development of MDD, and to assess both short- and long-term effects of modulating these mechanisms. We propose to examine immediate changes in stress reactivity, cognitive biases, and reward processing as a function of training. We also propose to conduct an 18-month follow-up assessment to examine longer-term effects of training on specific clinical constructs, such as levels of depressive symptoms, coping strategies, and the onset of MDD. This project will yield new insights concerning psychological and biological risk factors for MDD, and will provide important information that can be used to develop innovative and effective approaches to the prevention of depression. PUBLIC HEALTH RELEVANCE: This project promises to improve our understanding of psychological and biological mechanisms that increase risk for depression, a devastating psychiatric condition that affects one-quarter of the world's population, that starts early in life and frequently becomes chronic and unrelenting. Understanding these mechanisms will help us to develop more effective approaches to the prevention of clinical depression.

DESCRIPTION (provided by applicant): Adolescence is a period of high risk for the onset of Major Depressive Disorder (MDD); indeed, adolescent onset of MDD is associated with longer and more severe depressive episodes that are often refractory to treatment. Thus, it is imperative that we identify factors involved in early-onset MDD and develop more effective approaches to early intervention. In attempting to elucidate factors that contribute to the onset and maintenance of MDD, investigators have focused on negatively biased processing of information. The most consistent cognitive bias in depression involves more negative and less positive interpretations of emotionally ambiguous information. Importantly, investigators have shown not only that these biases in interpretation can be modified, but further, that Interpretatio Bias Training (IBT) improves emotion regulation and reduces depressive symptoms. Despite these findings, however, we know little about the mechanisms that underlie these positive effects of IBT. In an effort to gain a more comprehensive understanding of biased cognitive functioning in MDD, researchers have begun to examine neural aspects of biases in this disorder. In this context, investigators have documented abnormalities in function, connectivity, and/or structure in depressed adults in subgenual and dorsal anterior cingulate (ACC), dorsal prefrontal cortex (PFC), and amygdala, all components of emotion regulatory networks. To date, there is little research examining the neural foundations of cognitive biases in depressed children and adolescents or the effects of modifying these biases in depressed youth. The overarching goals of the proposed project are (1) to assess the cognitive, neural, and clinical effects of training designed to reduce negative interpretation biases in depressed adolescents; and (2) to examine neural and cognitive changes that mediate the positive clinical effects of IBT. Results of this project will increase our understanding of neural processes that underlie interpretation biases in depressed adolescents and contribute to the development of more effective interventions for MDD in adolescence.

DESCRIPTION (provided by applicant): Early life stress (ELS) is a significant risk factor for the development of a range of psychiatric symptoms that cut across a number of diagnostic categories. The mechanisms through which ELS confers this heightened vulnerability, however, are poorly understood. Given that there are several million referrals involving alleged child maltreatment in the US each year, it is critical that investigators focus on elucidating the neurodevelopmental consequences of ELS and the mechanisms by which ELS-related changes in neurobiological function confer vulnerability for psychopathology. Importantly, epidemiological studies have documented that the transition to puberty is a critical period for the expression of the effects of ELS; moreover, beginning at puberty, there is a higher incidence of symptoms of emotional disorders in females than in males who were abused as young children, suggesting that these outcomes are moderated by gender. Therefore, in efforts to elucidate the effects of ELS on neurobiological systems and on vulnerability for psychopathology, it is vital that researchers consider the impact of both puberty and gender. The proposed project is designed to address these issues, examining the influence of ELS on the maturation of neural circuits and neuroendocrine and cognitive processes that are critical to psychological health, and that are integral to specific RDoC constructs of the Negative Valence, Positive Valence, and Arousal/Regulatory Systems. Because ELS confers vulnerability for a range of psychiatric illnesses, elucidating the effects of ELS on broad domains of function in which aberrations are posited to transect a variety of psychopathologies will allow us to develop a more comprehensive and integrative understanding of how risk for psychopathology emerges and is manifested in children with a history of ELS. Further, findings from this project will inform early interventions aimed at preventing the long-term sequelae of ELS.

DESCRIPTION (provided by applicant): A behavioral hallmark of Major Depressive Disorder (MDD) is impaired gating of negative, task-irrelevant information. In previous work we documented that people with MDD exhibit impairments in controlling the entry of irrelevant negative information into working memory (WM) and in removing no-longer-relevant information from WM. Given the high prevalence and enormous costs of MDD, it is critical that we gain a better under- standing of the neural mechanisms that underlie these cognitive difficulties. Although investigators have begun to examine neural correlates of impaired information-gating processes in MDD, we do not yet understand the functional significance of these activations or the nature of their relation to depression, or consequently, how to leverage this knowledge to develop and evaluate individualized treatments for this heterogeneous disorder. We propose to use cutting-edge neuroimaging techniques to elucidate the neural mechanisms that underlie impaired gating of negative information in MDD, conducting innovative analyses of fMRI data (multi-voxel pattern analyses [MVPA] and functional connectivity) in order to quantify on a moment-to-moment basis the degree to which negative irrelevant information is represented in WM. This approach will allow us to test hypotheses about (a) specific large-scale networks that are posited to underlie information-gating deficits in MDD; and (b) the contribution of these networks to various clinical characteristics of MDD. Specifically, in two experiments we will elucidate the cognitive and neural mechanisms that underlie impaired gating in MDD during the entry of negative stimuli into WM, and during the removal of negative information from WM. Moreover, given findings in nondepressed populations that individual differences in the ability to gate task- irrelevant information are related to variations in goal-directed behavior, we further propose to assess the relation of individual differences in information gating to specific aspects of depressive symptomatology. We hypothesize that impaired gating of negative irrelevant information in MDD is associated with anomalous functioning of dorsal frontoparietal (top-down attentional control) and subcortical (emotional appraisal) networks during both the entry of negative information into WM and the removal of negative information from WM. We further hypothesize that these abnormalities are related to the specific depressive characteristics of emotion dysregulation, rumination, and negative affect, and to the severity of depressive symptoms. Importantly, our novel quantification of neural representations of negative information will move beyond coarse group-level assays to a more fine-grained individual-subject and trial-level understanding of the dynamic nature of the neurocognitive mechanisms that underlie MDD. Together, the proposed studies promise to 1) advance understanding of mechanisms that underlie the control of affective information in MDD; 2) inform theoretical models of the interaction of attention and emotion; and 3) facilitate the ultimate development of more effective, patient-specific interventions (e.g., cognitive or neural training) for major depression.

? DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is among the most prevalent and devastating of all psychiatric disorders, and is the single most burdensome disease worldwide. Consequently, it is imperative that we identify and examine the effects of altering mechanisms involved in the maintenance of MDD. In this context, investigators have documented that difficulty removing negative information from working memory is a core cognitive feature of MDD. Importantly, this cognitive difficulty is implicated in the persistence o both depressive symptoms and rumination, a style of thinking that hinders recovery from stress and exacerbates negative affect. To date, research linking difficulty removing negative information from working memory with rumination, the persistence of negative affect, and stress recovery in MDD has been limited by the use of correlational methodologies. Importantly, the Cognitive Bias Modification (CBM) literature underscores the viability of manipulating cognitive processes both to test causal relations and to identify mechanisms involved in the onset and maintenance of disorders. Therefore, a major aim of the proposed study is to build on established CBM methods to improve depressed individuals' ability to remove negative information (RNI) from working memory. We propose to examine the cognitive, affective, and biological effects of RNI training (Aim 1). In addition, we also propose to examine the neural mechanisms that underlie the beneficial effects of RNI training (Aim 2). To achieve these aims, 50 participants diagnosed with MDD will be assigned to receive either Real or Sham RNI training. All participants will complete pre-training laboratory-based and neuroimaging sessions, six at-home Real or Sham RNI training sessions, post-training laboratory-based and neuroimaging sessions, and a three-month follow-up assessment. We expect that, compared to Sham RNI training, Real RNI training will a) improve depressed participants' ability to remove negative information from working memory from pre- to post-training; b) decrease levels of rumination and depressive symptoms; and c) improve subsequent emotional and biological stress recovery. We further expect that RNI training will achieve its beneficial effects by decreasing brain activation from pre- to post-training in regions that subserve cognitive effort (dorsal anterior cingulate, posterior parietal lobe, and insular cortex), and by decreasing functional connectivity in regions posited to underlie rumination (subgenual anterior cingulate cortex and medial prefrontal cortex). The results of this study will increase our understanding of the relations among biases in working memory, rumination, and depressive symptoms, and will help to identify and elucidate specific mechanisms that contribute to the onset and maintenance of MDD.

Project Summary/Abstract Major Depressive Disorder (MDD) is a prevalent and debilitating illness. Risk for MDD is transmitted across familial generations; in fact, investigators have consistently documented a three- to six-fold increase in the risk for developing MDD in offspring of depressed parents. Although researchers have begun to examine mechanisms underlying this heightened familial risk for MDD, we still know little about the origins and the developmental course of abnormalities documented in children of depressed parents or about the specific parental behaviors that contribute to risk for psychopathology in offspring. The interactions between caregiver and infant represent the primary experience-dependent feature of the child?s early life. Given the plasticity of the infant brain, problematic or suboptimal caregiving during infancy is posited to create a developmental cascade, affecting normative brain trajectories, resulting in altered functioning in subsequent developmental stages, and increasing risk for psychopathology. We currently have little knowledge, however, about the effects of specific caregiving behaviors that characterize depressed parents on infant neural structure and function, and on infant stress reactivity and regulation, as measured by endocrine responses. In addressing this gap, we propose to adopt an RDoC framework to develop and examine a novel assessment of the quality of caregiving in early life and its relation to infant neural and endocrine systems implicated in the development of MDD. Specifically, two constructs from the RDoC Social Processes Domain, which have been linked to maternal depressive symptoms, are of interest: Perception and Understanding of Others; and Social Communication. We propose to recruit mother?infant dyads selected to vary in caregiver social processes. We will conduct a multi-method assessment that includes self-report, task-based, and laboratory-based measures of caregiver behaviors related to these two RDoC constructs. We will also conduct structural and functional MRI scans in infants, and will collect cortisol from infants during a laboratory-based social stressor. Thus, we will be able, for the first time, to integrate comprehensive measures of caregiver social processes, infant neural structure and function, and infant endocrine function. We predict that quality of caregiver empathy and communication will be associated with specific neural and endocrine characteristics in infants. Integrating assessments of maternal caregiving behaviors with infant neural and endocrine characteristics within an RDoC framework is critical for delineating the heterogeneity documented in the outcomes of offspring of depressed mothers. Findings from this project promise to yield specific insights concerning mechanisms involved in the early intergenerational transmission of risk for psychopathology and facilitate the development of more effective approaches to prevention and intervention in young children at risk for disorder.

Project Summary/Abstract Like other mammals, humans are dependent on environmental experiences to program our brains. For most humans, enriched and nurturing experiences provided by caregivers in the sensitive period of infancy provide sufficient stimulation to facilitate the formation of neural connections that further enable adaptive exploration and resilience in response to stress. Infants who experience deprivation in environmental stimulation (ES) and parental nurturance (PN), however, later exhibit aberrations in brain development and behavior. Despite the critical importance of the quantity and quality of caregiving experiences in early life, when the brain is developing most rapidly, we know little about how variations in ES and PN during infancy are selectively related to neural development and to stress-related endocrine function. The goal of this project is to conduct a multimethod assessment of ES and PN that includes naturalistic measurement of infant language exposure (including child-directed speech) and well-validated laboratory-based observations of caregiving behavior to infant distress. Importantly, we will link these measures to infant brain structure and function and endocrine responses to stress. Specifically, we propose to study 50 mother?infant dyads recruited to vary in levels of ES and PN provided to the infant in early life. We will use MRI to examine, for the first time, the specific neural correlates of both ES and PN during infancy. We will also examine infant HPA-axis reactivity and regulation to a stressful interaction in relation to variations in levels of ES and PN. We predict that lower levels of ES will be uniquely associated with reduced total gray matter volume and decreased fractional anisotropy in white matter fascicles responsible for interhemispheric communication and language processing. We also predict that lower levels of PN will be uniquely associated with reduced hippocampal volumes and reduced functional connectivity between emotion regulation regions as well as with greater amygdala activation in response to hearing negative emotional cues (i.e., mother?s angry voice). We predict further that infants who experience lower levels of PN will also exhibit greater HPA-axis reactivity and poorer HPA-axis regulation in response to stress. Findings from this project promise to yield critical insights about the role of early experience in shaping development by elucidating the impact of variations in ES and PN on the developing infant brain and HPA-axis functioning.

ABSTRACT The transition through adolescence is characterized by a striking increase in symptoms and rates of depression. In fact, the majority of first episodes of MDD occur during adolescence. One-quarter of adolescents experience an episode of Major Depressive Disorder (MDD) by the end of their teenage years, and almost half of adolescents with a depressive episode experience a recurrence within three years. In attempting to identify factors that contribute to this high prevalence of depression in adolescence, investigators have focused on the adverse effects of exposure to stress occurring during childhood, or early life stress (ELS). ELS, including abuse, neglect, parental loss, and interpersonal stress, is associated with a marked increase in risk for subsequent depression. We do not yet understand, however, the mechanisms by which ELS contributes to this risk, thus hampering effective prevention and intervention efforts with adolescents. The proposed project is designed to examine trajectories of two psychobiological mechanisms that may explain how ELS increases risk for depression during adolescence: increased stress reactivity and blunted reward sensitivity. This focus on the trajectories of stress and reward systems is particularly salient in adolescence given that both of these systems undergo significant change and reorganization during this sensitive period of development. We propose to follow longitudinally 220 boys and girls who have already completed two comprehensive assessments (beginning at 9 to 12 years of age), two years apart, of their exposure to ELS, psychobiological functioning (including behavioral, cognitive, endocrine, and neural assessments of stress reactivity and reward sensitivity), and MDD symptoms and diagnosis. We will leverage data obtained from this large and richly-characterized sample of children to examine prospectively the developmental mechanisms by which ELS affects the onset and course of depression during adolescence. Specifically, we will integrate data from the participants? first two assessments completed in late childhood and early adolescence with new data that we propose to obtain at two additional assessments conducted in mid and late adolescence, a developmental period during which the incidence of MDD peaks. Specifically, we will continue to assess clinical characteristics, information-processing biases, endocrine functioning, and brain function, structure, and connectivity. Collectively, this approach will allow us to analyze the effects of ELS on trajectories of psychobiological and clinical functioning from childhood through late adolescence, and on deviations from normative trajectories of these constructs. Findings from this project will inform efforts to generate personalized targets in order to tailor prevention and treatment programs to adolescents who have been exposed to ELS and who, consequently, are at high risk for developing MDD.

Project Summary/Abstract Women?s exposure to early life stress (ELS) can have lasting adverse consequences for emotional, cognitive, and biological functioning that extend into their child-bearing years. Emerging research suggests that the negative effects of ELS can be transmitted across generations, beginning in the prenatal period. In this project, we posit that mothers? exposure to stress during their own childhood affects the neurodevelopment of their offspring, first, by influencing the intrauterine endocrine milieu and, subsequently, through the process of dyadic physiological synchrony. Specifically, we posit that early exposure to life stress affects the pre- conception setpoint for the hypothalamic-pituitary-adrenal (HPA) axis, disrupting maternal levels and trajectories of cortisol across pregnancy and altering fetal neurodevelopment. We posit further that in the postnatal period infants continue to be affected by maternal HPA-axis dysregulation through concordance of their own HPA-axis functioning with that of their mothers. In this application, we propose conduct secondary analysis of banked samples of women?s hair obtained at three time-points: at mid-pregnancy, approximately 1 month after birth, and at infant age 6 months. From these samples, we will derive monthly levels of cortisol production across pregnancy and the early postnatal period, enabling us to examine the effects of maternal exposure to ELS on levels and trajectories of maternal hair cortisol concentration in the perinatal period and the effects of this cortisol production on both their infants? hair cortisol concentration and their infants? hippocampus and amygdala volume at age 6 months. This project promises to yield critical and specific insights, informing our understanding of maternal factors that affect child neurodevelopment.