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

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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.