Early Life Stress and Depression: Molecular and Functional Imaging Approaches

项目摘要 流行病学研究表明，严重的童年逆境可以解释32%-44%的精神障碍， 在晚年患抑郁症的风险是4.6倍，滥用药物的风险是6.6倍。尽管 这些流行病学数据，与环孢素A的不良适应后遗症相关的神经生物学基础 在很大程度上仍然不为人知。临床前研究强烈表明，早期的逆境导致(1)结构性 与应激调节密切相关的内侧前额叶皮质区域的异常；(2)增加 氧化应激；(3)谷氨酸能异常。目前的竞争更新是专门设计的 前瞻性地测试这些异常在接触CsA的个体中的作用。加在一起，这些 研究将检验以下假设：“免疫氧化”机制内的异常，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。 局部神经元回路失衡和关键区域形态异常(MPFC)；(2) 与关键的MDD表型相关；(3)前瞻性地预测未来的症状和功能。这些 目标将通过评估12-16岁之间有CSA病史的年轻成年女性来实现 确诊为重度抑郁症的现任(“MDD/CSA”组)或既往(“rMDD/CSA”组)年限 无序。为了弄清CsA与MDD相关的影响，这些组将与两个健康对照组进行比较 无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磁共振波谱(MRS)集成的4T扫描仪(以量化 氧化还原比率和体内脑生物能量学)，高场多核MRS(评估谷氨酸代谢物和 谷胱甘肽)、功能磁共振成像(探索无享乐行为的神经关联和 认知控制缺陷)。为了跟踪疾病进程，所有参与者都将在6岁和12岁时接受前瞻性评估 一个月的后续会议。根据我们广泛的初步发现，我们假设，相对于 无论是健康对照组还是MDD组，MDD/CSA患者的大脑皮质都会变薄。 内侧前额叶皮质，较低的氧化还原比率，较低的谷氨酰胺/谷氨酸比率，以及较高的炎症标志物 (假设1)。我们进一步预计，这些异常将持续存在于心境良好的rMDD/CSA受试者中， 特别是随着终生抑郁发作的数量不断增加。此外，我们预计这些 异常将与更多的非享乐行为和认知缺陷有关(假设2)，以及 将在后续评估中预测非享乐性症状、认知缺陷和较差的总体功能 (假设3)。提高我们对不同环孢素A相关神经生物学机制的理解 结果是至关重要的，以便(1)确定有精神病理风险的个人和 适应不良行为，(2)防止再次受害，(3)开发更有针对性的治疗干预措施。

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.