In the past decade, experimental studies involving healthy human volunteers have revealed that manipulations of the central serotonin (5-HT) system can produce quite specific changes in cognitive functioning, independent of overt mood changes. Reduced 5-HT turnover is consistently associated with impaired long-term memory functioning. Low 5-HT function may also impair cognitive flexibility and improve focused attention. On the other hand, stimulation of central 5-HT has repeatedly been found to impair performance in a true vigilance task. Currently, there is little evidence for mirrored cognitive changes due to opposite 5-HT manipulations in healthy volunteers. Given the mounting evidence for a role of 5-HT in human cognition, reduced 5-HT function could be directly linked to cognitive disturbances in certain conditions, such as in depression and Alzheimer's Disease (AD). There is evidence that stimulating (i.e. normalizing) 5-HT activity in depression may have specific beneficial effects on cognition, independent of a general relief of depressive symptoms, but this premise needs to be confirmed by larger-scale clinical studies. Recently, a potential role of 5-HT in the cognitive symptoms in AD has been identified, but there is insufficient data to evaluate the effects of 5-HT stimulation on cognitive symptoms in AD. It is concluded that serotonin is a potential target for pharmacological cognition enhancement, particularly for restoration of impaired cognitive performance due to 5-HT dysfunction. Further differentiation of the role of 5-HT in normal and disturbed cognition and evaluation of the effects of 5-HT manipulations in various populations is required to establish the full potential of 5-HT drugs as cognition enhancers.

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The depressed patients receiving long-term treatment with SSRI- and SNRI-type antidepressants show impaired driving performance. This impairment in driving performance can probably be attributed to residual depressive symptoms instead of the antidepressant treatment.

The default-mode network (DMN), which comprises medial frontal, temporal and parietal regions, is part of the brain’s intrinsic organization. The serotonergic (5-HT) neurotransmitter system projects to DMN regions from midbrain efferents, and manipulation of this system could thus reveal insights into the neurobiological mechanisms of DMN functioning. Here, we investigate intrinsic functional connectivity of the DMN as a function of activity of the serotonergic system, through the administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram. We quantified DMN functional connectivity using an approach based on dual-regression. Specifically, we decomposed group data of a subset of the functional time series using spatial independent component analysis, and projected the group spatial modes to the same and an independent resting state time series of individual participants. We found no effects of escitalopram on global functional connectivity of the DMN at the map-level; that is, escitalopram did not alter the global functional architecture of the DMN. However, we found that escitalopram decreased DMN regional pairwise connectivity, which included anterior and posterior cingulate cortex, hippocampal complex and lateral parietal regions. Further, regional DMN connectivity covaried with alertness ratings across participants. Our findings show that escitalopram altered intrinsic regional DMN connectivity, which suggests that the serotonergic system plays an important role in DMN connectivity and its contribution to cognition. Pharmacological challenge designs may be a useful addition to resting-state functional MRI to investigate intrinsic brain functional organization.

BackgroundSeveral neighbourhood elements have been found to be related to leisure-time walking and cycling. However, the association with neighbourhood safety remains unclear. This study aimed to assess the association of neighbourhood-level safety with leisure-time walking and cycling among Dutch adults.MethodsData were derived from the national health survey (POLS) 2006–2009, with valid data on 20046 respondents residing in 2127 neighbourhoods. Multilevel logistic regression models were used to examine the association between neighbourhood-level safety (general safety and specific safety components: physical disorder, social disorder, crime-related fear, traffic safety) and residents’ engagement in outdoor leisure-time walking and cycling for at least 30 minutes per week.ResultsAn increase in neighbourhood safety (both general safety and each of the safety components) was significantly associated with an increase in leisure-time cycling participation. Associations were strongest for general safety and among older women. In the general population, neighbourhood safety was not significantly associated with leisure-time walking. However, among younger and older adult men and lower educated individuals, an increase in general safety was associated with a decrease in leisure-time walking participation.ConclusionsIn the Netherlands, neighbourhood safety appears to be related to leisure-time cycling but not to walking. Leisure-time cycling may best be encouraged by improving different safety components at once, rather than focusing on one safety aspect such as traffic safety. Special attention is needed for older women.

Prospective memory refers to the realization of delayed intentions. Several studies have shown that 3,4-methylenedioxy-methamphetamine (MDMA) users perform worse on measures of prospective memory as compared to nondrug users. Interpretation of these data may be limited because of polydrug use, psychosocial stressors, and increased psychopathology that have been reported in MDMA users. This study was designed to directly assess the pharmacological effect of MDMA on prospective memory and brain activity in a double-blind, placebo-controlled, cross-over study. Twelve recreational MDMA users received MDMA 75 mg and placebo and performed an objective prospective memory task during functional imaging. During prospective memory task performance subjects were engaged in a foreground task that consisted of a simple reaction time to visual stimuli (Go trials) and a prospective task of withholding a response during trials that were part of a dynamic memory set (No go trials). Behavioral data showed that a single dose of MDMA increased prospective memory failures in the No go trials, and that number of prospective memory failures was positively correlated to MDMA concentration in plasma. Functional imaging showed that MDMA decreased BOLD activation during Go trials in the thalamus (left), putamen (left), precuneus (left), and the inferior parietal lobules (bilateral), as compared to placebo. During No go trials, MDMA reduced BOLD deactivation in the inferior parietal lobules (bilateral), as compared to placebo. It is concluded that the loss of deactivation in inferior parietal lobules may account for increments in memory failures observed during MDMA intoxication.

The results of the current pharmaco-functional magnetic resonance imaging (fMRI) study give a first indication of involvement of serotonin in sustained attention through modulating activation of selective brain areas including the thalamus and caudate nucleus. Possibly, these areas are involved in a subcortical network for sustained attention, but further research is necessary.

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