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.

项目概要流行病学研究表明，32-44% 的精神疾病是由严重的童年逆境造成的，尽管如此，与以后生活中患抑郁症的风险增加 4.6 倍，滥用药物的风险增加 6.6 倍有关。这些流行病学数据是与 CSA 适应不良后遗症相关的神经生物学基础临床前研究强烈表明，早期的逆境会导致（1）结构性的。内侧前额皮质异常与压力调节密切相关（2）增加；氧化应激；和（3）谷氨酸异常当前的竞争性更新是专门设计的。前瞻性地测试这些异常对暴露于 CSA 的个体的影响。研究将检验“免疫氧化”机制异常的假设，包括异常氧化还原调节、氧化应激和谷氨酸代谢物的平衡与 MDD 和 CSA 相关我们预计这些异常之间的相互作用 (1) 会导致兴奋/抑制。局部神经回路失衡和关键区域的形态异常（mPFC）（2）；与关键的 MDD 表型相关；(3) 前瞻性预测未来的症状和功能。将通过评估 12-16 岁之间有 CSA 病史的年轻成年女性来实现目标当前（“MDD/CSA”组）或以前（“rMDD/CSA”组）诊断为重度抑郁症的年数为了区分 CSA 与 MDD 相关的影响，这些组将与健康对照进行比较。没有 CSA 病史的 MDD 女性（“MDD”组）所有受试者 (N=160) 将在 3T 和 3T 进行测试。 4T 扫描仪集成了最先进的 31P 磁共振波谱 (MRS)（以量化体内氧化还原比和脑生物能学），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（探索快感缺乏行为的神经相关性和认知控制缺陷）。为了追踪疾病进程，所有参与者都将在 6 岁和 12 岁进行前瞻性评估。根据我们广泛的初步调查结果，我们认为，相对于无论是健康对照组还是 MDD 组，MDD/CSA 个体在内侧前额皮质，氧化还原比较低，谷氨酰胺/谷氨酸比较低，炎症标志物较高（假设 1）。我们进一步预计这些异常将在心境正常的 rMDD/CSA 受试者中持续存在，特别是随着终生抑郁发作次数的增加，我们预计这些情况也会发生。异常将与快感缺乏行为和认知缺陷增加相关（假设 2），并且将在后续评估中预测快感缺失症状、认知缺陷和较差的整体功能（假设 3）。提高我们对不同 CSA 相关神经生物学机制的理解。结果至关重要，以便 (1) 识别有精神病理学风险的个体；适应不良行为，(2) 防止再次受害，(3) 制定更有针对性的治疗干预措施。