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 1H-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.

Figures

Figure 1

Model for effects of estradiol and LDX on executive function. Executive functioning capacity depends on the neurochemical environment in the PFC. Within the optimum range of neurotransmitter concentrations, represented by the gray crosshatching in the figure, normal executive functioning is maintained by a balance of factors including dopamine, norepinephrine, and glutamate concentrations as well as estradiol level. Where a woman falls on this curve depends on her genetics for catecholaminergic and glutamatergic metabolism and signaling as well as hormonal status and stress level. Response to stress is modified by numerous factors such as age, hormonal and reproductive status, current or previous use of medications such as glucocorticoids or psychoactive drugs, smoking, coffee and alcohol consumption, caloric intake, genetics, exposure to prenatal stress, birth weight, gestational age, level of early family adversity, and position in social hierarchy, indicating that individual lifestyle choices and adverse childhood experiences may affect an individual's executive functioning capacity before and during menopause (reviewed by Kudielka et al, 2009). In addition, factors such as depressive symptoms (Culpepper, 2015), substance use, and medication side effects (Kudielka et al, 2009) may also contribute to an individual's executive functioning capacity. During menopause, women whose combination of such factors place them toward the left of the optimal range may experience executive functioning difficulties because of loss of estradiol modulation of prefrontal systems. LDX may improve executive functioning in these women by increasing dopamine and norepinephrine as well as decreasing glutamate in the PFC, although response to LDX should be considered in the context of underlying genetic variability in catecholaminergic and glutamatergic neurotransmission.

Figure 2

LDX improves subjective measures of executive function. The decrease in BADDS scores from baseline was significantly greater with LDX versus placebo for both (a) total BADDS (F=26.6, df=13, P<0.0002) and (b) each BADDS subscale (organization/activation for work, F=14.3, df=13, P=0.002; attention/concentration, F=31.7, df=13, P<0.0001; alertness/effort/processing speed, =12.3, df=13, P=0.004; managing affective interference, F=4.8, df=13, P=0.05; working memory/accessing recall, F=14.4, df=13, P=0.002). Error bars represent standard error.

Figure 3

LDX increases executive activation during working memory. (a) The n-back task robustly activated executive network regions and deactivated non-executive regions, as depicted by the parametric contrast (z>4.5, P<0.001). (b) Recruitment of the right insula and left DLPFC increased with increasing levels of working memory load. Values plotted represent mean difference in activation from baseline at each task level. Error bars represent SD. (c) Whole-brain analysis using a paired t-test (z>1.6, P<0.05) of the 3-back contrast demonstrated that activation in the right insula (MNI coordinates: x=48, y=52, z=18; k=1416) was significantly greater than placebo. (d) LDX-induced increase in both right insula and left DLPFC BOLD signal from baseline during the 3-back was positively correlated with LDX-induced decrease in total BADDS Scores as well as BADDS subscales measuring organization/activation for work and alertness/effort/processing speed. Subjects with the greatest improvements in BADDS scores demonstrated less task-induced activation with LDX, whereas subjects with the least improvements in BADDS scores demonstrated greater task-induced activation with LDX. Right insula: total BADDS (r=0.95, P⩽0.0001, t=9.88, df=11); organization/activation for work (r=0.86, P=0.0004, t=5.22, df=11); alertness/effort/processing speed (r=0.83, P=0.0008, t=4.70, df=11). Left DLPFC: total BADDS (r=0.78, P=0.003, t=3.90, df=11); organization/activation for work (r=0.78, P=0.0028, t=3.93, df=11); alertness/effort/processing speed (r=0.81, P=0.0014, t=4.38, df=11).

Figure 4

Left DLPFC Glx concentrations. (a) Decrease in left DLPFC Glx concentration from baseline was greater with LDX vs placebo (F=4.5, df=12, P=0.056). Error bars represent standard error. (b) At baseline, left DLPFC Glx concentration was positively correlated with total BADDS (r=0.64, P=0.01, t=2.90, df=13) as well as BADDS subscales measuring organization/activation for work (r=0.70, P=0.005, t=3.43, df=13) and alertness/effort/processing speed (r=0.58, P=0.03, t=2.47, df=13).