Grant Number:	5R01CA215587-05 Interpret this number
Primary Investigator:	Epperson, C. Neill
Organization:	University Of Pennsylvania
Project Title:	Multi-Modal Imaging of Psychostimulant Effects on Executive Function Post-Rrso
Fiscal Year:	2021

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.




Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine.
Authors: Metcalf C.A. , Page C.E. , Stocker B.O.S. , Johnson R.L. , Duffy K.A. , Sammel M.D. , Loughead J. , Epperson C.N. .
Source: Gynecologic Oncology, 2024-08-14 00:00:00.0; 190, p. 62-69.
EPub date: 2024-08-14 00:00:00.0.
PMID: 39146756
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Natural vs. surgical postmenopause and psychological symptoms confound the effect of menopause on executive functioning domains of cognitive experience.
Authors: Page C.E. , Soreth B. , Metcalf C.A. , Johnson R.L. , Duffy K.A. , Sammel M.D. , Loughead J. , Epperson C.N. .
Source: Maturitas, 2023 Apr; 170, p. 64-73.
EPub date: 2023-02-06 00:00:00.0.
PMID: 36806931
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Adverse childhood experiences and hormonal contraception: Interactive impact on sexual reward function.
Authors: Novick A.M. , Stoddard J. , Johnson R.L. , Duffy K.A. , Berkowitz L. , Costa V.D. , Sammel M.D. , Epperson C.N. .
Source: Plos One, 2023; 18(1), p. e0279764.
EPub date: 2023-01-17 00:00:00.0.
PMID: 36649369
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Discontinuation of hormonal contraception due to changes in mood and decreases in sexual desire: the role of adverse childhood experiences.
Authors: Novick A.M. , Johnson R.L. , Lazorwitz A. , Belyavskaya A. , Berkowitz L. , Norton A. , Sammel M.D. , Epperson C.N. .
Source: The European Journal Of Contraception & Reproductive Health Care : The Official Journal Of The European Society Of Contraception, 2022-02-08 00:00:00.0; , p. 1-9.
EPub date: 2022-02-08 00:00:00.0.
PMID: 35133231
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Influences of the menopause transition and adverse childhood experiences on peripheral basal inflammatory markers.
Authors: Metcalf C.A. , Johnson R.L. , Freeman E.W. , Sammel M.D. , Epperson C.N. .
Source: Brain, Behavior, & Immunity - Health, 2021 Aug; 15, p. 100280.
EPub date: 2021-06-01 00:00:00.0.
PMID: 34589780
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Germ Cell Drivers: Transmission of Preconception Stress Across Generations.
Authors: Duffy K.A. , Bale T.L. , Epperson C.N. .
Source: Frontiers In Human Neuroscience, 2021; 15, p. 642762.
EPub date: 2021-07-12 00:00:00.0.
PMID: 34322003
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Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs.
Authors: Morgan C.P. , Shetty A.C. , Chan J.C. , Berger D.S. , Ament S.A. , Epperson C.N. , Bale T.L. .
Source: Scientific Reports, 2020-10-15 00:00:00.0; 10(1), p. 17498.
EPub date: 2020-10-15 00:00:00.0.
PMID: 33060642
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Neuropsychiatric effects of tamoxifen: Challenges and opportunities.
Authors: Novick A.M. , Scott A.T. , Neill Epperson C. , Schneck C.D. .
Source: Frontiers In Neuroendocrinology, 2020-08-18 00:00:00.0; 59, p. 100869.
EPub date: 2020-08-18 00:00:00.0.
PMID: 32822707
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Executive function after risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: does current mood and early life adversity matter?
Authors: Shanmugan S. , Sammel M.D. , Loughead J. , Ruparel K. , Gur R.C. , Brown T.E. , Faust J. , Domchek S. , Epperson C.N. .
Source: Menopause (new York, N.y.), 2020 Jul; 27(7), p. 746-755.
PMID: 32187134
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Filling the Regulatory Gap: Potential Role of Institutional Review Boards in Promoting Consideration of Sex as a Biological Variable.
Authors: Duffy K.A. , Ziolek T.A. , Epperson C.N. .
Source: Journal Of Women's Health (2002), 2020 06; 29(6), p. 868-875.
EPub date: 2020-04-08 00:00:00.0.
PMID: 32267784
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