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：
10418734
负责人：
FEI DU
金额：
$ 77.43万
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/10418734
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 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 Stressful Event Structural defect 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 maladaptive behavior 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.

项目摘要流行病学研究表明，严重的儿童广告解释了32-44％的精神疾病，并与抑郁症的4.6倍和6.6倍以后的药物滥用风险有关。尽管这些流行病学数据，与CSA不良后遗症有关的神经生物学基础在很大程度上未知。临床前研究强烈表明，早期的广告导致（1）结构内侧前额叶皮层区域的异常与压力调节有关；（2）增加氧化应激；（3）谷氨酸能异常。当前的竞争更新是专门设计的前瞻性测试暴露于CSA的个体中这些异常的贡献。在一起，这些研究将检验“免疫氧化”机制中异常的假设，包括异常氧化还原调节，氧化应激和谷氨酸代谢产物的平衡与MDD和CSA有关病理生理学。我们期望这些异常之间的相互作用（1）导致兴奋性/抑制性关键区域内局部神经元电路和形态异常的不平衡（MPFC）；（2）是与关键MDD表型相关；（3）前瞻性预测未来的症状和功能。这些通过评估年龄在12-16岁之间的CSA历史的年轻女性，将实现目标与当前（“ MDD/CSA”组）或以前（“ RMDD/CSA”组）的年份诊断紊乱。为了解散CSA-与MDD相关的效果，将将这些组与两个健康对照组进行比较和没有CSA病史的MDD女性（“ MDD”组）。所有受试者（n = 160）将在3T和使用最先进的31p磁共振光谱（MRS）的整合的4T扫描仪（以量化氧化还原比和体内脑生物能学），高场多核MRS（评估谷氨酸代谢物和谷胱甘肽），功能性磁共振成像（探测Anhedonic行为的神经元相关性和认知控制定义）。为了跟踪疾病课程，所有参与者将在6-和12--中进行评估。一个月的随访课程。根据我们广泛的初步发现，我们假设相对于健康对照组和MDD组，MDD/CSA个体都会显示出更大的皮质变薄培养基前皮层，较低的氧化还原比，较低的谷氨酰胺/谷氨酸比和较高的炎症标记（假设1）。我们进一步期望这些异常将持续存在于正式的RMDD/CSA受试者中，特别是随着终生抑郁发作数量增加。而且，我们希望这些异常将与增加的厌氧行为和认知缺陷有关（假设2）和在后续评估中，将预测厌氧症状，认知定义和较差的一般功能（假设3）。提高我们对与不同CSA相关的神经生物学机制的理解结果对于（1）确定有心理病理学风险的人和适应不良的行为，（2）防止复活，（3）产生更有针对性的治疗干预措施。