Sex-dependent multimodal response profiles to psychosocial stress.

INTRODUCTION: Sex differences in stress reactions are often reported in the literature. However, the sex-dependent interplay of different facets of stress is still not fully understood. Particularly in neuroimaging research, studies on large samples combining different indicators of stress remain scarce. MATERIALS AND METHODS: In a functional magnetic resonance imaging study, a sample of 140 healthy participants (67 females using oral contraceptives) underwent a standardized stress induction protocol, the ScanSTRESS. During the experiment, salivary cortisol and subjective ratings were obtained at multiple time points and heart rate was recorded. RESULTS: Sex differences emerged in different facets of the stress response:Women reacted with enhanced subjective feelings of stress and increases in heart rate, while men showed more pronounced neural activation in stress-related brain regions such as the inferior frontal gyrus and insula. Subjective feelings of stress and (para) hippocampal activity were negatively related in women,whereas a slightly positive association was observed in men. DISCUSSION: These results provide further insight in the sex-specific stress response patterns. Moreover, they emphasize the role of the hippocampus in the regulation of the stress response. This paves the way for the identification of sex-dependent vulnerability factors that can, in the future, be implemented in the prevention and treatment of stress-related disorders.

Fast accurate quantification of salivary cortisol and cortisone in a large-scale clinical stress study by micro-UHPLC-ESI-MS/MS using a surrogate calibrant approach.

Cortisol and cortisone are common markers for stress and thus preferentially analyzed in matrices that allow non-invasive sampling such as saliva. Though the major drawback of immunoassays is lack of specificity due to cross reactivities, they are still most commonly used for quantification of steroid hormones. To overcome such problems, sensitive methods based on liquid chromatography-mass spectrometry are becoming more and more accepted as the golden standard for steroid bioanalysis as they achieve accurate quantification at trace levels for multiple analytes in the same run. Along this line, the aim of this study was the development of a new microflow UHPLC-ESI-MS/MS method for the measurement of salivary cortisol and cortisone, which due to its microflow regime provides enhanced sensitivity and is more ecofriendly. The developed method implemented sample preparation by Solid-Phase Extraction (SPE) in a 96-well plate format. Data acquisitions were carried out in MRM (multiple reaction monitoring) mode. The quantitative determination of endogenous compounds in saliva remains a challenge since analyte-free matrix is lacking. Hence, a surrogate calibrant approach with cortisol-d4 andcortisone-13C3 was applied for the target compounds in the presented method. A number of factors were optimized and the method validated. The lower limit of quantitation (LLOQ) was 72 and 62 pg mL-1for cortisol and cortisone, respectively. Linear calibration was achieved in the range from 0.062 to 75.5 ng mL-1for cortisol-d4 and 0.072 to 44 ng mL-1forcortisone-13C3. The performance of the method was also evaluated via proficiency test for salivary cortisol. Finally, it was applied successfully to evaluate cortisol and cortisone concentrations in multiple batches in routine clinical stress study samples (4056 total injections with 1983 study samples). Moreover, the instrument performance (in particular retention time variability) within each batch, between different batches and lot-to-lot of 5 investigated capillary columns over time is described. The work documents that micro-UHPLC-ESI-MS/MS is suitable and robust enough to carry out a full clinical study with greater than 1000s of samples over an extended period if adequate internal standards can be used.

The association of the 5-HTTLPR polymorphism and the response to different stressors in healthy males.

The experience of stress is related to individual wellbeing and vulnerability to psychopathology. Therefore, understanding the determinants of individual differences in stress reactivity is of great concern from a clinical perspective. The functional promotor polymorphism of the serotonin transporter gene (5-HTTLPR/rs25531) is such a factor, which has been linked to the acute stress response as well as the adverse effect of life stressors. In the present study, we compared the impact of two different stress induction protocols (Maastricht Acute Stress Test and ScanSTRESS) and the respective control conditions on affective ratings, salivary cortisol levels and cognitive performance. To this end, 156 healthy young males were tested and genotyped for the 5-HTTLPR/rs25531 polymorphism. While combined physiological and psychological stress in the MAST led to a greater cortisol increase compared to control conditions as well as the psychosocial ScanSTRESS, subjective stress ratings were highest in the ScanSTRESS condition. Stress induction in general affected working memory capacity but not response inhibition. Subjective stress was also influenced by 5-HTTLPR/rs25531 genotype with the high expression group showing lower stress ratings than lower expression groups. In line with previous research, we identified the low expression variant of the serotonin transporter gene as a risk factor for increased stress reactivity. While some dimensions of the human stress response may be stressor specific, cognitive outcomes such as working memory performance are influenced by stress in general. Different pathways of stress processing and possible underlying mechanisms are discussed.

Sleep strengthens integration of spatial memory systems.

Spatial memory comprises different representational systems that are sensitive to different environmental cues, like proximal landmarks or local boundaries. Here we examined how sleep affects the formation of a spatial representation integrating landmark-referenced and boundary-referenced representations. To this end, participants (n = 42) were familiarized with an environment featuring both a proximal landmark and a local boundary. After nocturnal periods of sleep or wakefulness and another night of sleep, integration of the two representational systems was tested by testing the participant's flexibility to switch from landmark-based to boundary-based navigation in the environment, and vice versa. Results indicate a distinctly increased flexibility in relying on either landmarks or boundaries for navigation, when familiarization to the environment was followed by sleep rather than by wakefulness. A second control study (n = 45) did not reveal effects of sleep (vs. wakefulness) on navigation in environments featuring only landmarks or only boundaries. Thus, rather than strengthening isolated representational systems per se, sleep presumably through forming an integrative representation, enhances flexible coordination of representational subsystems.

Imaging stress: an overview of stress induction methods in the MR scanner.

Processing of acute stress has potential implications for mental and physical health. At the same time, individuals differ largely in how strongly they react to stress. Neuroimaging paradigms have been developed to characterize the neural underpinnings of the stress response in general and to understand the mechanisms that differentiate high and low susceptible individuals. The goal of the present review was to summarize the current literature on psychosocial stress in the brain imaging environment. That is, we focused on the most common neuroimaging paradigms that have been used to induce acute stress and map out the questions that have been addressed with respect to the determinants, the consequences, and the processing of stress. We identified four major paradigms that have been used with different scientific aims. The Montreal Imaging Stress Test and the ScanSTRESS involve cognitive challenge and social-evaluative threat and yielded a stress-related network including most significantly the perigenual ACC, the hippocampus, and the amygdala. The social-evaluative threat paradigm was used to predict the autonomic stress response on the basis of multivariate pattern analysis. The aversive video paradigm, on the other hand, was mainly used to investigate the consequences of stress on emotional and cognitive processes and their neural correlates. We conclude our review with a critical evaluation of methodological and conceptual issues in the study of the neural correlates of acute stress.

Exploring the fMRI based neural correlates of the dot probe task and its modulation by sex and body odor.

The dot probe task implicitly cues attention via emotional information, an effect which is especially pronounced for threat-related cues. However, several questions remain unexplored. The first one is whether chemosignals like the androgen-derivative androstadienone can influence such attentional biases. Second, few studies have addressed sex differences regarding attentional biases. Finally, the neural correlates of these potential behavioral effects based on functional magnetic resonance imaging (fMRI) are not known. In two experiments we aimed to answer these questions. A total of 159 healthy individuals (58 oral-contraceptive-users, 42 luteal women, 59 men) were tested. In experiment 1 (behavioral study) we examined attentional biases behaviorally, while in experiment 2 (fMRI study) the dot probe task was complemented by fMRI. Our results provide robust evidence that in healthy participants fearful but not angry or happy faces lead to a strong general attentional bias. Elucidating the neural basis of this effects points to an early processing advantage in bilateral thalamus for valid compared to invalid cued fear. However, this finding was limited to those participants with the strongest attentional biases and was not linked to behavioral measures. Furthermore, no consistent sex or group differences existed neither did the putative human chemosignal androstadienone reliably modulate attentional biases or change neural processing.

Sleep augments training-induced improvement in working memory in children and adults.

Sleep plays an important role in forming procedural motor memories. Whether sleep plays a similar role for cognitive procedures related to working memory function, is not yet clear. Here we investigated if sleep enhances training-induced improvements in working memory in children. Because children show more intense slow wave sleep (e.g., higher slow wave activity, more spindles) we expected sleep-related improvements to be greater than in adults. Twenty-four children (10-12 years) and 24 adults were trained on three sessions of an n-back task comprising three runs of blocks (6 blocks with 20 responses each) presented in ascending levels of difficulty. The sessions were separated by ∼12 h. Between the training sessions, participants first spent a full night sleeping and then a normal day awake (evening groups) or vice versa (morning groups). We analyzed performance on the whole blocks and, to estimate the individual's optimum performance, on only the first 10 trials of each block. Results showed a distinct gain in training-induced working memory performance with post-training overnight sleep compared to wakefulness. The sleep-induced gain was revealed only for performance on the first block-halves and, in absolute terms, was closely comparable in children and adults. Taking differences in working memory performance into account sleep-dependent gains expressed as percentages of baseline performance were, however, greater in children than in adults. The data thus indicate that sleep after training facilitates cognitive procedures related to executive control, i.e., the ability to operate sequences of events in working memory, with a particular benefit in developing populations.

Bayesian informed evidence against modulation of androstadienone-effects by genotypic receptor variants and participant sex: A study assessing Stroop interference control, mood and olfaction.

The androgen derivative androstadienone (AND) is present in human sweat and may act as human chemosignal. Though effects of AND have been reported with respect to emotional and cognitive processes, results have been highly inconsistent. For this reason, it is likely that AND-action is dependent on modulatory factors. Here we wanted to specifically investigate the impact of genotypic variations of the AND-receptor OR7D4, as well as the influence of participant sex and concomitant hormonal fluctuations on AND-action during emotional interference processing, olfactory performance and mood assessments. To this end 80 healthy individuals (women taking oral contraceptives; naturally cycling women measured during the luteal phase and men) were tested twice on two consecutive days (AND vs. placebo exposure) with an emotional Stroop task. Also, olfactory performance and mood was assessed. Participants provided saliva samples to measure testosterone, progesterone and estradiol and a blood sample to assess genotypic variations of the AND-receptor OR7D4. We found a small task-dependent reduction of overall error rates under AND but no modulation of effects by genetic variation or group (female OC, female NC, male) with respect to olfactory performance and mood. Additional analyses with help of Bayesian statistics gave strong evidence in favor of specific null hypotheses suggesting that the action of AND was not modulated by either genotypic variations or sex of participants with respect to interference control (bias indices), olfactory self-reports and mood parameters. Additional effects of AND in connection with hormonal fluctuations are reported.

Effects of Sleep on Word Pair Memory in Children - Separating Item and Source Memory Aspects.

Word paired-associate learning is a well-established task to demonstrate sleep-dependent memory consolidation in adults as well as children. Sleep has also been proposed to benefit episodic features of memory, i.e., a memory for an event (item) bound into the spatiotemporal context it has been experienced in (source). We aimed to explore if sleep enhances word pair memory in children by strengthening the episodic features of the memory, in particular. Sixty-one children (8-12 years) studied two lists of word pairs with 1 h in between. Retrieval testing comprised cued recall of the target word of each word pair (item memory) and recalling in which list the word pair had appeared in (source memory). Retrieval was tested either after 1 h (short retention interval) or after 11 h, with this long retention interval covering either nocturnal sleep or daytime wakefulness. Compared with the wake interval, sleep enhanced separate recall of both word pairs and the lists per se, while recall of the combination of the word pair and the list it had appeared in remained unaffected by sleep. An additional comparison with adult controls (n = 37) suggested that item-source bound memory (combined recall of word pair and list) is generally diminished in children. Our results argue against the view that the sleep-induced enhancement in paired-associate learning in children is a consequence of sleep specifically enhancing the episodic features of the memory representation. On the contrary, sleep in children might strengthen item and source representations in isolation, while leaving the episodic memory representations (item-source binding) unaffected.

10-Month-Old Infants Are Sensitive to the Time Course of Perceived Actions: Eye-Tracking and EEG Evidence.

Research has shown that infants are able to track a moving target efficiently - even if it is transiently occluded from sight. This basic ability allows prediction of when and where events happen in everyday life. Yet, it is unclear whether, and how, infants internally represent the time course of ongoing movements to derive predictions. In this study, 10-month-old crawlers observed the video of a same-aged crawling baby that was transiently occluded and reappeared in either a temporally continuous or non-continuous manner (i.e., delayed by 500 ms vs. forwarded by 500 ms relative to the real-time movement). Eye movement and rhythmic neural brain activity (EEG) were measured simultaneously. Eye movement analyses showed that infants were sensitive to slight temporal shifts in movement continuation after occlusion. Furthermore, brain activity associated with sensorimotor processing differed between observation of continuous and non-continuous movements. Early sensitivity to an action's timing may hence be explained within the internal real-time simulation account of action observation. Overall, the results support the hypothesis that 10-month-old infants are well prepared for internal representation of the time course of observed movements that are within the infants' current motor repertoire.

Sleep enhances knowledge of routes and regions in spatial environments.

Sleep is thought to preferentially consolidate hippocampus-dependent memory, and as such, spatial navigation. Here, we investigated the effects of sleep on route knowledge and explicit and implicit semantic regions in a virtual environment. Sleep, compared with wakefulness, improved route knowledge and also enhanced awareness of the semantic regionalization within the environment, whereas signs of implicit regionalization remained unchanged. Results support the view that sleep specifically enhances explicit aspects of memory, also in the spatial domain. Enhanced region knowledge after sleep suggests that consolidation during sleep goes along with the formation of more abstract schema-like representations.

On the validity and generality of transfer effects in cognitive training research.

Evaluation of training effectiveness is a long-standing problem of cognitive intervention research. The interpretation of transfer effects needs to meet two criteria, generality and specificity. We introduce each of the two, and suggest ways of implementing them. First, the scope of the construct of interest (e.g., working memory) defines the expected generality of transfer effects. Given that the constructs of interest are typically defined at the latent level, data analysis should also be conducted at the latent level. Second, transfer should be restricted to measures that are theoretically related to the trained construct. Hence, the construct of interest also determines the specificity of expected training effects; to test for specificity, study designs should aim at convergent and discriminant validity. We evaluate the recent cognitive training literature in relation to both criteria. We conclude that most studies do not use latent factors for transfer assessment, and do not test for convergent and discriminant validity.

Comparing manual and automatic segmentation of hippocampal volumes: reliability and validity issues in younger and older brains.

We compared hippocampal volume measures obtained by manual tracing to automatic segmentation with FreeSurfer in 44 younger (20-30 years) and 47 older (60-70 years) adults, each measured with magnetic resonance imaging (MRI) over three successive time points, separated by four months. Retest correlations over time were very high for both manual and FreeSurfer segmentations. With FreeSurfer, correlations over time were significantly lower in the older than in the younger age group, which was not the case with manual segmentation. Pearson correlations between manual and FreeSurfer estimates were sufficiently high, numerically even higher in the younger group, whereas intra-class correlation coefficient (ICC) estimates were lower in the younger than in the older group. FreeSurfer yielded higher volume estimates than manual segmentation, particularly in the younger age group. Importantly, FreeSurfer consistently overestimated hippocampal volumes independently of manually assessed volume in the younger age group, but overestimated larger volumes in the older age group to a less extent, introducing a systematic age bias in the data. Age differences in hippocampal volumes were significant with FreeSurfer, but not with manual tracing. Manual tracing resulted in a significant difference between left and right hippocampus (right > left), whereas this asymmetry effect was considerably smaller with FreeSurfer estimates. We conclude that FreeSurfer constitutes a feasible method to assess differences in hippocampal volume in young adults. FreeSurfer estimates in older age groups should, however, be interpreted with care until the automatic segmentation pipeline has been further optimized to increase validity and reliability in this age group.

Age-related differences in temporal and spatial dimensions of episodic memory performance before and after hundred days of practice.

Normal aging impairs the representation and integration (binding) of spatial and temporal context in episodic memory. We directly compare age differences in episodic memory in relation to processing spatial and temporal context. As part of the COGITO study, 101 younger and 103 older participants trained an object-location serial recall task for 100 sessions. Training exacerbated the recall deficit of older relative to younger adults. Younger adults improved in recall performance on both spatial and temporal dimensions. In contrast, older adults improved on the spatial dimension only. Individual differences in pretest performance and change were positively correlated across dimensions among younger adults but negatively related among older adults. We conclude that older adults are impaired at simultaneously processing spatial and temporal context and preferentially process spatial at the expense of temporal context.

The dynamics of change in striatal activity following updating training.

Increases in striatal activity have been suggested to mediate training-related improvements in working-memory ability. We investigated the temporal dynamics of changes in task-related brain activity following training of working memory. Participants in an experimental group and an active control group, trained on easier tasks of a constant difficulty in shorter sessions than the experimental group, were measured before, after about 1 week, and after more than 50 days of training. In the experimental group an initial increase of working-memory related activity in the functionally defined right striatum and anatomically defined right and left putamen was followed by decreases, resulting in an inverted u-shape function that relates activity to training over time. Activity increases in the striatum developed slower in the active control group, observed at the second posttest after more than 50 days of training. In the functionally defined left striatum, initial activity increases were maintained after more extensive training and the pattern was similar for the two groups. These results shed new light on the relation between activity in the striatum (especially the putamen) and the effects of working memory training, and illustrate the importance of multiple measurements for interpreting effects of training on regional brain activity.

Normal aging increases discriminal dispersion in visuospatial short-term memory.

Computational models of cognitive aging propose that age-related decrements in cognitive performance, including short-term memory (STM), result from less distinct stimulus representations. When applied to visual STM, these models predict higher discriminal dispersion (L. L. Thurstone, 1927, Psychophysical analysis, The American Journal of Psychology, 38, 368-389.) in older adults than in younger adults. To test this prediction, we used a change-detection paradigm for visuospatial locations, with different levels of cognitive load (one, three, or five items) and retention interval (100 or 1,000 ms). Adult age differences were not reliable at Load 1, but were substantial at Loads 3 and 5. Effects of retention time did not differ across age groups, suggesting that age-related differences originated mainly from early processing stages. Applying a mixture model to the data revealed age-related increases in discriminal dispersion and decreases in asymptotic discrimination performance (indexing STM capacity). We concluded that age-related declines in discriminal dispersion, in addition to increasing capacity limitations, impair visual STM performance with advancing adult age.

Cortical thickness changes following spatial navigation training in adulthood and aging.

A widespread network involving cortical and subcortical brain structures forms the neural substrate of human spatial navigation. Most studies investigating plasticity of this network have focused on the hippocampus. Here, we investigate age differences in cortical thickness changes evoked by four months of spatial navigation training in 91 men aged 20-30 or 60-70 years. Cortical thickness was automatically measured before, immediately after, and four months after termination of training. Younger as well as older navigators evidenced large improvements in navigation performance that were partly maintained after termination of training. Importantly, training-related cortical thickening in left precuneus and paracentral lobule were observed in young navigators only. Thus, spatial navigation training appears to affect cortical brain structure of young adults, but there is reduced potential for experience-dependent cortical alterations in old age.

Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood.

It is unknown whether lifestyle, including mental stimulation, and appropriate training interventions, may directly improve spatial navigation performance and its underlying neural substrates. Here we report that healthy younger and older men performing a cognitively demanding spatial navigation task every other day over 4 months display navigation-related gains in performance and stable hippocampal volumes that were maintained 4 months after termination of training. In contrast, control groups displayed volume decrements consistent with longitudinal estimates of age-related decline. Hippocampal barrier density, as indicated by mean diffusivity estimated from diffusion tensor imaging, showed a quadratic shape of increased density after training followed by a return to baseline in the right hippocampus, but declined in the control groups and in the left hippocampus. We conclude that sustained experiential demands on spatial ability protect hippocampal integrity against age-related decline. These results provide the first longitudinal evidence indicating that spatial navigation experience modifies hippocampal volumes in humans, and confirm epidemiological results suggesting that mental stimulation may have direct effects on neural integrity.

Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

Cognitive plasticity in adulthood and old age: gauging the generality of cognitive intervention effects.

Interventions enabling aging individuals to fulfill their plastic potential promise to postpone, attenuate, or even reverse the adverse effects of senescent brain changes on cognitive abilities and everyday competence in old age. Based on an overview of the concept of plasticity in lifespan development, we selectively review evidence from cognitive intervention studies and conclude that most of them have failed to observe generalizable performance improvements, as documented by the small size and scope of positive transfer to untrained tasks. We further note that generally accepted criteria for defining transfer distance are lacking, rendering the relevant evidence difficult to interpret. Hence, we propose a taxonomy of transfer distance based on the structure of human intellectual abilities.