Multi-Modal Imaging of Psychostimulant Effects on Executive Function Post-RRSO

项目总结：完成输卵管切除术后降低风险的双侧输卵管卵巢切除术（RRSO） 生育已成为预防妇科和乳腺癌的标准护理 BRCA 1或BRCA 2基因突变携带者。尽管手术可以降低因死亡而死亡的风险， 超过75%的癌症，关于这一过程的影响和随后的知识， 性腺功能减退对脑结构、功能和神经递质系统的影响有限。更年期 在40岁之前，与随后几年的认知能力下降有关， 如果女性不补充雌二醇（E2），患痴呆症的风险增加近2倍 然而，由于癌症风险增加，E2不是许多RRSO后女性的选择。 对一大批接受RRSO的妇女进行的系统评估表明， 执行功能（EF）缺陷，严重程度与RRSO时的年龄呈负相关。为 前额叶皮层受到E2损失的影响，对工作记忆和其他EF至关重要，我们 我建议研究精神兴奋剂对生物和行为的影响 利右苯丙胺（LDX）在100名35 - 55岁RRSO术后EF女性中的应用 投诉参与者将接受多模态成像（功能磁共振 核磁共振波谱（1H-MRS） 高磁场强度7特斯拉前后6周的精神兴奋剂课程 利右旋苯丙胺（LDX; Vyvanse®）或安慰剂，然后在交叉前进行3周洗脱 到另一个条件。我们的首要目标是确定LDX治疗对 大脑功能（神经激活和化学），因为它涉及到主观和客观 EF的措施，如1）组织和激活工作，2）注意力和集中， 3)警觉性，努力，处理速度，4）管理情感干扰，5）工作 记忆，访问回忆。虽然非传统的精神兴奋剂的使用，这本小说 这种方法已经证明了改善新发EF困难的潜力， 经历了自然绝经期的妇女，并提供了关于 潜在的治疗作用机制，特别是LDX诱导的背外侧 前额叶皮层（dlPFC）谷氨酸（GLUT）水平。

Project Summary: Risk-reduction bilateral salpingo-oophorectomy (RRSO) after completion of childbearing has become the standard-of-care for prevention of gynecologic and breast cancer in BRCA1 or BRCA2 gene mutation carriers. Although surgery reduces the risk of death due to cancer by over 75%, knowledge regarding the impact of this procedure and subsequent hypogonadism on brain structure, function and neurotransmitter systems is limited. Menopause before the age of 40 is associated with significant cognitive decline in the years that follow and an almost 2-fold increased risk of dementia if a woman does not supplement with estradiol (E2) However, E2 is not an option for many post-RRSO women due to enhanced risk of cancer. Systematic assessment of a large group of women who underwent RRSO suggests subjective deficits in executive functions (EF), with severity inversely correlated with age at RRSO. As the prefrontal cortex is impacted by loss of E2 and is critical for working memory and other EFs, we propose to examine the biological and behavioral impact of the psychostimulant lisdexamfetamine (LDX) in 100 women between the ages of 35 and 55 with post-RRSO EF complaints. Participants will undergo multi-modal imaging (functional magnetic resonance spectroscopy, fMRI; and proton magnetic resonance spectroscopy, 1H-MRS) using the ultra- high magnetic field strength of 7 Tesla pre and post a 6-week course of the psychostimulant lisdexamphetamine (LDX; Vyvanse®) or placebo followed by a 3-week washout before crossing over to the other condition. Our overarching aim is to determine the impact of LDX treatment on brain function (neural activation and chemistry) as it relates to subjective and objective measures of EFs such as 1) organization and activation for work, 2) attention and concentration, 3) alertness, effort, processing speed, 4) managing affective interference, and 5) working memory, accessing recall. While an unconventional use of psychostimulants, this novel approach has already demonstrated the potential to improve new-onset EF difficulties among women who underwent a natural menopause and has provided important information regarding a potential mechanism of therapeutic action, specifically LDX-induced changes in dorsolateral prefrontal cortex (dlPFC) glutamate (GLUT) levels.