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Studies have long reported that aging is associated with declines in several functions modulated by the prefrontal cortex, including executive functions like working memory, set shifting, and inhibitory control. The neurochemical basis to this is poorly understood, but may include the serotonergic system. We investigated the modulatory effect of serotonin using acute tryptophan depletion (ATD) during a cognitive switching task involving visual-spatial set shifting modified for a functional MRI environment. Ten healthy women over 55 years were tested on two separate occasions in this within-group double-blind sham-controlled crossover study to compare behavioral and physiological brain functioning following ATD and following a ("placebo") sham depletion condition. ATD did not significantly affect task performance. It did modulate brain functional recruitment. During sham depletion women significantly activated the expected task-relevant brain regions associated with the Switch task including prefrontal and anterior cingulate cortices. In contrast, following ATD participants activated posterior regions of brain more during switch than repeat trials. In addition to the main effects of depletion condition, a comparison of the ATD relative to the sham condition confirmed this anterior-to-posterior shift in activation. The posterior (increased) activation clusters significantly and negatively correlated with the reduced prefrontal activation clusters suggesting a compensation mechanism for reduced prefrontal activation during ATD. Thus, serotonin modulates an anterior-to-posterior shift of activation during cognitive switching in older adults. Neural adaptation to serotonin challenge during cognitive control may prove useful in determining cognitive vulnerability in older adults with a predisposition for serontonergic down-regulation (e.g., in vascular or late life depression)., (Copyright © 2012 Wiley Periodicals, Inc.)

Age-related declines in prefrontal functions and age-related declines in prefrontal serotonin (5-HT) are documented. The effect of 5-HT on prefrontal cortex (PFC) is also documented; however, no one has examined the effect of experimental 5-HT modulation on PFC in healthy older adults. We investigated the effect of 5-HT on brain functioning in 10 women over 55 (mean=63.0+/-5.3 years) during cognitive interference inhibition (Simon task) using fMRI and acute tryptophan depletion (ATD). ATD did not affect task performance; it did affect brain function. During sham/no depletion, participants activated brain regions associated with the Simon (e.g., left inferior PFC). During ATD, there was no prefrontal but alternative posterior brain activation. ATD relative to sham reduced activity in left inferior PFC, anterior cingulate and basal ganglia but increased activity within neocerebellum and parietal lobe. In older adults, ATD modulates task-relevant brain activation for cognitive interference inhibition and is associated with an anterior-to-posterior activation shift. Maintaining successful Simon performance during ATD is achieved by increasing cerebellar and parietal contributions to compensate for decreased fronto-cingulo-striatal involvement.

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.