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Early Life Stress and Depression: Molecular and Functional Imaging Approaches

早期生活压力和抑郁：分子和功能成像方法

基本信息

批准号：
10203785
负责人：
FEI DU
金额：
$ 77.28万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10203785
关键词：
Adolescence Adult Affect Age Anhedonia Animals Award Behavior Behavior Control Behavioral Bioenergetics Brain Brain region Child Child Sexual Abuse Cognitive deficits Communities Computer Models Corpus striatum structure Coupled Data Depressed mood Diagnosis Disease Equilibrium Event Exposure to Female Frequencies Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Future Glutamates Glutamine Glutathione Goals Health Hippocampus (Brain)Human Imaging Techniques Individual Inflammatory Lead Learning Life Link Magnetic Resonance Spectroscopy Major Depressive Disorder Maps Medial Mental Depression Mental disorders Molecular Neurobiology Outcome Oxidation-Reduction Oxidative Stress Participant Pathway interactions Phenotype Prefrontal Cortex Process Psychopathology Recording of previous events Regulation Reporting Rewards Risk Rodent Role Sampling Sexual abuse Stress Structural defect Structure Substance abuse problem Symptoms Testing Therapeutic Intervention Thick Thinness Time Transcriptional Regulation Woman base biobehavior childhood adversity cognitive control cytokine depressive symptoms design dopamine transporter early life adversity early life stress epidemiologic data epidemiology study experience follow up assessment follow-up imaging approach improved in vivo inflammatory marker meetings molecular imaging negative affect neural correlate neurobiological mechanism neuronal circuitry novel physical abuse pre-clinical pre-clinical research predictive marker prevent prospective prospective test revictimization targeted treatment young adult

项目摘要

Project Summary Epidemiological studies have shown that severe childhood adversity explains 32-44% of psychiatric disorders, and is associated with 4.6-fold risk for depression and 6.6-fold risk for substance abuse later in life. In spite of these epidemiological data, the neurobiological underpinnings associated with maladaptive sequelae of CSA remain largely unknown. Preclinical research strongly suggests that early adversity leads to (1) structural abnormalities in medial prefrontal cortex regions critically implicated in stress regulation; (2) increased oxidative stress; and (3) glutamatergic abnormalities. The current competing renewal was specifically designed to prospectively test the contributions of these abnormalities in individuals exposed to CSA. Together, these studies will test the hypotheses that abnormalities within “immuno-oxidative” mechanisms, including abnormal balance of redox regulation, oxidative stress and glutamate metabolites are linked to MDD and CSA pathophysiology. We expect that interactions among these abnormalities (1) lead to excitatory/inhibitory imbalance of local neuronal circuits and morphometrical abnormalities within key regions (mPFC); (2) are associated with key MDD phenotypes; and (3) prospectively predict future symptoms and functioning. These goals will be achieved by evaluating young adult females with a history of CSA between the ages of 12-16 years with a current (“MDD/CSA” group) or former (“rMDD/CSA” group) diagnosis of major depressive disorder. To disentangle CSA- vs. MDD-related effects, these groups will be compared to both healthy controls and MDD females without a history of CSA (“MDD” group). All subjects (N=160) will be tested at both 3T and 4T scanners using an integration of state-of-the-art 31P magnetic resonance spectroscopy (MRS) (to quantify redox ratio and brain bioenergetics in vivo), high field multinuclear MRS (to assess glutamate metabolites and glutathione), functional magnetic resonance imaging (to probe the neural correlates of anhedonic behavior and cognitive control deficits). To track disease course, all participants will be prospectively assessed at 6- and 12- month follow-up sessions. Based on our extensive set of preliminary findings, we hypothesize that, relative to both healthy controls and the MDD group, MDD/CSA individuals will show greater cortical thinning in the medial prefrontal cortex, lower redox ratio, lower glutamine/glutamate ratio, and higher inflammatory markers (Hypothesis 1). We further expect that these abnormalities will persist in euthymic rMDD/CSA subjects, particularly with increasing number of lifetime depressive episodes. Moreover, we expect that these abnormalities will be associated with increased anhedonic behavior and cognitive deficits (Hypotheses 2), and will predict anhedonic symptom, cognitive deficits and poorer general functioning at the follow-up assessments (Hypothesis 3). Improving our understanding of neurobiological mechanisms associated with different CSA outcomes is of paramount importance in order to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent revictimization, and (3) develop more targeted therapeutic interventions.

项目总结