Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties

Abstract

Many women with no history of executive dysfunction report difficulties in this domain during the menopause transition. Lisdexamfetamine (LDX) has been suggested to be a safe and effective treatment option for these women. However, the mechanism by which LDX improves executive functioning in these women is not known. Here we investigated the effects of LDX on brain activation and neurochemistry, hypothesizing that LDX would be associated with increased activation and decreased glutamate in executive regions. Fourteen women underwent multimodal neuroimaging at 7T at three time points in this baseline-corrected, double-blind, placebo-controlled, crossover study. Effects of LDX on symptom severity, blood-oxygen-level-dependent (BOLD) signal, and dorsolateral prefrontal cortex (DLPFC) glutamate + glutamine (Glx) were measured using a clinician-administered questionnaire, fMRI during performance of a fractal n-back task, and 1 H-MRS, respectively. The effect of treatment (LDX minus baseline vs placebo minus baseline) on these behavioral and neural markers of executive function was examined using repeated measures mixed effects models. LDX treatment was associated with decreased symptom severity, increased activation in the insula and DLPFC, and decreased DLPFC Glx. In addition, the magnitude of LDX-induced improvement in symptom severity predicted both direction and magnitude of LDX-induced change in insular and DLPFC activation. Moreover, symptom severity was positively correlated with Glx concentration in the left DLPFC at baseline. These findings provide novel evidence that the neural mechanisms by which LDX acts to improve self-reported executive functioning in healthy menopausal women with midlife onset of executive difficulties include modulation of insular and DLPFC recruitment as well as decrease in DLPFC Glx concentration.

Gender-Affirming Hormone Use in Transgender Individuals: Impact on Behavioral Health and Cognition

“…Specifically, gonadal steroids can have great impact on brain structure, function, regional connectivity, and neurochemistry [14], which influences executive functions, affect, and reward processing. The prefrontal cortex—the site of estrogen modulation of executive function—is essential for cognitive processes such as sustained attention, working memory, organization, and planning [14, 31, 62]. FTM individuals taking high-dose testosterone and left in a hypoestrogenic and hypertestosteronic state could be at risk for executive dysfunction, as exhibited in cisgender females experiencing premature loss of estradiol or polycystic ovary syndrome, respectively [63,64].…”

“…Based on the literature in cisgender populations, it is known that estradiol, testosterone, and progesterone—as well as its neurosteroid metabolite allopregnanolone (Allo)—have strong influence on neurotransmitter levels and receptors, as well as neuronal and glial architecture and function in presumably cisgender individuals [14, 30, 31]. Since changes in these gonadal and adrenal steroid levels can profoundly affect cognition and mood [14, 32], exogenous hormone administration by GAHT must further be studied to better inform patients about potential changes in executive functioning and behavioral health.…”

Ovarian hormones: a long overlooked but critical contributor to cognitive brain structures and function

“…Finally, both estrogen and progestagens are neuromodulators, and have been shown to interact with neurotransmitters, including dopamine, serotonin, gamma‐aminobutyric acid, glutamate, and acetylcholine . Though challenging to study in humans, the rise of spectroscopy provides intriguing possibilities for future investigations …”

Impact of early life adversity and tryptophan depletion on functional connectivity in menopausal women: A double-blind, placebo-controlled crossover study

“…First, we focused on middle-aged females who were within 10 years of their final menstrual period, as women are at risk of executive dysfunction during the menopause transition (Epperson et al, 2015; Shanmugan and Epperson, 2014; Shanmugan et al, 2017b). Given the impact of estradiol on prefrontal cortex structure and function (Shanmugan and Epperson, 2014) as well as evidence for sex differences in the effects of early adversity (Shanmugan and Satterthwaite, 2016) on neural response, these data cannot be extrapolated to similar-aged males or pre-menopausal females.…”

“…Several reports have suggested that healthy women with no history of cognitive dysfunction experience increased difficulty with everyday tasks requiring executive processes such as working memory, focus, attention, organization, and planning (Epperson et al, 2015; Shanmugan and Epperson, 2014; Shanmugan et al, 2017b). There is preliminary evidence for adverse childhood experiences (ACE) such as abuse, neglect, and household dysfunction as a risk factor for executive dysfunction during this hormonal transition (Shanmugan and Epperson, 2014).…”