The brain’s pre-stimulus default state interacts with working memory in a load-dependent manner

Recently, multiple studies showed that spatial and temporal features of a task-negative default mode network (DMN) (Greicius et al., 2003) are important markers for psychiatric diseases (Balsters et al., 2013). Another prominent indicator of cognitive functioning, yielding information about the mental condition in health and disease, is working memory (WM) processing. In EEG and MEG studies, frontal-midline theta power has been shown to increase with load during WM retention in healthy subjects (Brookes et al., 2011). Negative correlations between DMN activity and theta amplitude have been found during resting state (Jann et al., 2010) as well as during WM (Michels et al., 2010). Likewise, WM training resulted in higher resting state theta power as well as increased small-worldness of the resting brain (Langer et al., 2013). Further, increased fMRI connectivity between nodes of the DMN correlated with better WM performance (Hampson et al., 2006). Hence, the brain’s default state might influence it’s functioning during task. We therefore hypothesized correlations between pre-stimulus DMN activity and EEG-theta power during WM maintenance, depending on the WM load. 17 healthy subjects performed a Sternberg WM task while being measured simultaneously with EEG and fMRI. Data was recorded within a multicenter-study: 12 subjects were measured in Zurich with a 64-channels MR-compatible system (Brain Products) in a 3T Philips scanner, 5 subjects with a 96-channel MR-compatible system (Brain Products) in a 3T Siemens Scanner in Bern. The DMN components was obtained by a group BOLD-ICA approach over the full task duration (figure 1). The subject-wise dynamics were obtained by back-reconstructed onto each subject’s fMRI data and normalized to percent signal change values. The single trial pre-stimulus-DMN activation was then temporally correlated with the single trial EEG-theta (3-8 Hz) spectral power during retention intervals. This so-called covariance mapping (Jann et al., 2010) yielded the spatial distribution of the theta EEG fluctuations during retention associated with the dynamics of the pre-stimulus DMN. In line with previous findings, theta power was increased at frontal-midline electrodes in high- versus low-load conditions during early WM retention (figure 2). However, correlations of DMN with theta power resulted in primarily positive correlations in low-load conditions, while during high-load conditions negative correlations of DMN activity and theta power were observed at frontal-midline electrodes. This DMN-dependent load effect reached significance in the middle of the retention period (TANOVA, p<0.05) (figure 3). Our results show a complex and load-dependent interaction of pre-stimulus DMN activity and theta power during retention, varying over time. While at a more global, load-independent view pre-stimulus DMN activity correlated positively with theta power during retention, the correlation was inversed during certain time windows in high-load trials, meaning that in trials with enhanced pre-stimulus DMN activity theta power decreases during retention. Since both WM performance and DMN activity are markers of mental health our results could be important for further investigations of psychiatric populations.

Normal values for pancreatic stone protein in different age groups.

BACKGROUND Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.

Cognitive rehabilitation of working memory in juvenile multiple sclerosis-effects on cognitive functioning, functional MRI and network related connectivity.

PURPOSE To assess possible effects of working memory (WM) training on cognitive functionality, functional MRI and brain connectivity in patients with juvenile MS. METHODS Cognitive status, fMRI and inter-network connectivity were assessed in 5 cases with juvenile MS aged between 12 and 18 years. Afterwards they received a computerized WM training for four weeks. Primary cognitive outcome measures were WM (visual and verbal) and alertness. Activation patterns related to WM were assessed during fMRI using an N-Back task with increasing difficulty. Inter-network connectivity analyses were focused on fronto-parietal (left and right), default-mode (dorsal and ventral) and the anterior salience network. Cognitive functioning, fMRI and inter-network connectivity were reassessed directly after the training and again nine months following training. RESULTS Response to treatment was seen in two patients. These patients showed increased performance in WM and alertness after the training. These behavioural changes were accompanied by increased WM network activation and systematic changes in inter-network connectivity. The remaining participants were non-responders to treatment. Effects on cognitive performance were maintained up to nine months after training, whereas effects observed by fMRI disappeared. CONCLUSIONS Responders revealed training effects on all applied outcome measures. Disease activity and general intelligence may be factors associated with response to treatment.

The effect of thyroxine and triiodothyronine on fatigue, depression, and memory in a hypothyroid population

Background. This study was planned at a time when important questions were being raised about the adequacy of using one hormone to treat hypothyroidism instead of two. Specifically, this trial aimed to replicate prior findings which suggested that substituting 12.5 μg of liothyronine for 50 μg of levothyroxine might improve mood, cognition, and physical symptoms. Additionally, this trial aimed to extend findings to fatigue. ^ Methods. A randomized, double-blind, two-period, crossover design was used. Hypothyroid patients stabilized on levothyroxine were invited to participate. Thirty subjects were recruited and randomized. Sequence one received their standard levothyroxine dose in one capsule and placebo in another during the first six weeks. Sequence two received their usual levothyroxine dose minus 50 μg in one capsule and 10 μg of liothyronine in another. At the end of the first six week period, subjects were crossed over. T tests were used to assess carry-over and treatment effects. ^ Results. Twenty-seven subjects completed the trial. The majority of completers had an autoimmune etiology. Mean baseline levothyroxine dose was 121 μg/d (±26.0). Subjects reported small increases in fatigue as measured by the Piper Fatigue Scale (0.9, p = 0.09) and in symptoms of depression measured by the Beck Depression Inventory-II (2.3, p = 0.16) as well as the General Health Questionnaire-30 (4.7, p = 0.14) while treated with substitution treatment. However, none of these differences was statistically significant. Measures of working memory were essentially unchanged between treatments. Thyroid stimulating hormone was about twice as high during substitution treatment (p = 0.16). Free thyroxine index was reduced by 0.7 (p < 0.001), and total serum thyroxine was reduced by 3.0 (p < 0.001) while serum triiodothyronine was increased by 20.5 (p < 0.001) on substitution treatment. ^ Conclusions. Substituting an equivalent amount of liothyronine for a portion of levothyroxine in patients with hypothyroidism does not decrease fatigue, symptoms of depression, or improve working memory. However, due to changes in serum hormone levels and small increments in fatigue and depression symptoms on substitution treatment, a question was raised about the role of T3 in the serum. ^

The contributions of the hippocampal formation, perirhinal cortex and areas TH/TF to object, spatial and contextual recognition memory in primates

Adult monkeys (Macaca mulatta) with lesions of the hippocampal formation, perirhinal cortex, areas TH/TF, as well as controls were tested on tasks of object, spatial and contextual recognition memory. ^ Using a visual paired-comparison (VPC) task, all experimental groups showed a lack of object recognition relative to controls, although this impairment emerged at 10 sec with perirhinal lesions, 30 sec with areas TH/TF lesions and 60 sec with hippocampal lesions. In contrast, only perirhinal lesions impaired performance on delayed nonmatching-to-sample (DNMS), another task of object recognition memory. All groups were tested on DNMS with distraction (dDNMS) to examine whether the use of active cognitive strategies during the delay period could enable good performance on DNMS in spite of impaired recognition memory (revealed by the VPC task). Distractors affected performance of animals with perirhinal lesions at the 10-sec delay (the only delay in which their DNMS performance was above chance). They did not affect performance of animals with areas TH/TF lesions. Hippocampectomized animals were impaired at the 600-sec delay (the only delay at which prevention of active strategies would likely affect their behavior). ^ While lesions of areas TH/TF impaired spatial location memory and object-in-place memory, hippocampal lesions impaired only object-in-place memory. The pattern of results for perirhinal cortex lesions on the different task conditions indicated that this cortical area is not critical for spatial memory. ^ Finally, all three lesions impaired contextual recognition memory processes. The pattern of impairment appeared to result from the formation of only a global representation of the object and background, and suggests that all three areas are recruited for associating information across sources. ^ These results support the view that (1) the perirhinal cortex maintains storage of information about object and the context in which it is learned for a brief period of time, (2) areas TH/TF maintain information about spatial location and form associations between objects and their spatial relationship (a process that likely requires additional time) and (3) the hippocampal formation mediates associations between objects, their spatial relationship and the general context in which these associations are formed (an integrative function that requires additional time). ^

Impact of oral contraceptives on weight, body composition, and cardiovascular disease risk factors in women age 18--30 years participating in a 15-week exercise program

Objective. To assess differences in body weight, body composition, total cholesterol, blood pressure, and blood glucose between OC users and non-users age 18-30 y before and after a 15-week cardiovascular exercise program in Houston, TX from 2003 to 2007.^ Study Design. Secondary analysis of prospective data. ^ Study Subjects. 453 Non-Hispanic white (NHW), Hispanic, and African American (AA) women age 18-30 y with no previous live birth, a history of menstruating, no use of other hormonal contraceptives or medications, no menopause or hysterectomy, and no current pregnancies.^ Measurements. Demographic data, medication use, and menstrual history were assessed via self-administered questionnaires at baseline. Anthropometric and laboratory measures were taken at baseline and 15-weeks. ^ Data Analysis. Linear regression assessed the association between OC use and study variables at baseline, and the change in study variables from baseline to 15-weeks. Logistic regression assessed the association between OC use and CVD risk. Each analysis was also stratified by race/ethnicity. ^ Results. At baseline, OC users had higher total cholesterol (p<.0005) and were above cholesterol risk cut points for CVD (OR=4.3, 95% CI=2.4-7.7) compared to non-users. At baseline, OC use was also associated with higher diastolic blood pressure (p=.018) compared to non-users, primarily in non-Hispanic whites (p=.007). OC use was associated with lower blood glucose compared to non-users in Hispanics only (p=.008). OC use was associated with absolute change in diastolic blood pressure (p=.044) and total cholesterol (p=.003). There was evidence that OC use may affect individuals differently based on race/ethnicity for certain obesity and CVD risk factors.^ Conclusions. OC users and non-users responded similarly to a 15-week cardiovascular exercise program. Exceptions included a greater change in diastolic blood pressure and total cholesterol among NHW and Hispanic OC users compared to non-users after exercise intervention. At baseline, OC use was associated with diastolic blood pressure and was most strongly associated with increased levels of total cholesterol. OC users were at greater risk of having total cholesterol above CVD risk cut points than non-users.^

STUDIES ON CHOLINERGIC FUNCTION AND MEMORY IN MICE (CHOLINOTOXINS, WORKING, REFERENCE MEMORY, RADIAL ARM MAZE)

Considerable evidence suggests that central cholinergic neurons participate in either acquisition, storage or retrieval of information. Experiments were designed to evaluate information processing in mice following either reversible or irreversible impairment in central cholinergic activity. The cholinergic receptor antagonists, atropine and methylatropine were used to reversibly inhibit cholinergic transmission. Irreversible impairment in central cholinergic function was achieved by central administration of the cholinergic-specific neurotoxins, N-ethyl-choline aziridinium (ECA) and N-ethyl-acetylcholine aziridinium (EACA).^ ECA and EACA appear to act by irreversible inhibition of high affinity choline uptake (proposed rate-limiting step in acetylcholine synthesis). Intraventricular administration of ECA or EACA produced persistent reduction in hippocampal choline acetyltransferase activity. Other neuronal systems and brain regions showed no evidence of toxicity.^ Mice treated with either ECA or EACA showed behavioral deficits associated with cholinergic dysfunction. Passive avoidance behavior was significantly impaired by cholinotoxin treatment. Radial arm maze performance was also significantly impaired in cholinotoxin-treated animals. Deficits in radial arm maze performance were transient, however, such that rapid and apparent complete behavioral recovery was seen during retention testing. The centrally active cholinergic receptor antagonist atropine also caused significant impairment in radial arm maze behavior, while equivalent doses of methylatropine were without effect.^ The relative effects of cholinotoxin and receptor antagonist treatment on short-term (working) memory and long-term (reference) memory in radial arm maze behavior were examined. Maze rotation studies indicated that there were at least two different response strategies which could result in accurate maze performance. One strategy involved the use of response algorithms and was considered to be a function of reference memory. Another strategy appeared to be primarily dependent on spatial working memory. However, all behavioral paradigms with multiple trails have reference memory requirements (i.e. information useful over all trials). Performance was similarly affected following either cholinotoxin or anticholinergic treatment, regardless of the response strategy utilized. In addition, rates of behavioral recovery following cholinotoxin treatment were similar between response groups. It was concluded that both cholinotoxin and anticholinergic treatment primarily resulted in impaired reference memory processes. ^

Effects of air pollution on asthma hospitalization rates in different age groups in metropolitan cities of Korea

Many studies have shown relationships between air pollution and the rate of hospital admissions for asthma. A few studies have controlled for age-specific effects by adding separate smoothing functions for each age group. However, it has not yet been reported whether air pollution effects are significantly different for different age groups. This lack of information is the motivation for this study, which tests the hypothesis that air pollution effects on asthmatic hospital admissions are significantly different by age groups. Each air pollutant's effect on asthmatic hospital admissions by age groups was estimated separately. In this study, daily time-series data for hospital admission rates from seven cities in Korea from June 1999 through 2003 were analyzed. The outcome variable, daily hospital admission rates for asthma, was related to five air pollutants which were used as the independent variables, namely particulate matter <10 micrometers (μm) in aerodynamic diameter (PM10), carbon monoxide (CO), ozone (O3), nitrogen dioxide (NO2), and sulfur dioxide (SO2). Meteorological variables were considered as confounders. Admission data were divided into three age groups: children (<15 years of age), adults (ages 15-64), and elderly (≥ 65 years of age). The adult age group was considered to be the reference group for each city. In order to estimate age-specific air pollution effects, the analysis was separated into two stages. In the first stage, Generalized Additive Models (GAMs) with cubic spline for smoothing were applied to estimate the age-city-specific air pollution effects on asthmatic hospital admission rates by city and age group. In the second stage, the Bayesian Hierarchical Model with non-informative prior which has large variance was used to combine city-specific effects by age groups. The hypothesis test showed that the effects of PM10, CO and NO2 were significantly different by age groups. Assuming that the air pollution effect for adults is zero as a reference, age-specific air pollution effects were: -0.00154 (95% confidence interval(CI)= (-0.0030,-0.0001)) for children and 0.00126 (95% CI = (0.0006, 0.0019)) for the elderly for PM 10; -0.0195 (95% CI = (-0.0386,-0.0004)) for children for CO; and 0.00494 (95% CI = (0.0028, 0.0071)) for the elderly for NO2. Relative rates (RRs) were 1.008 (95% CI = (1.000-1.017)) in adults and 1.021 (95% CI = (1.012-1.030)) in the elderly for every 10 μg/m3 increase of PM10 , 1.019 (95% CI = (1.005-1.033)) in adults and 1.022 (95% CI = (1.012-1.033)) in the elderly for every 0.1 part per million (ppm) increase of CO; 1.006 (95%CI = (1.002-1.009)) and 1.019 (95%CI = (1.007-1.032)) in the elderly for every 1 part per billion (ppb) increase of NO2 and SO2, respectively. Asthma hospital admissions were significantly increased for PM10 and CO in adults, and for PM10, CO, NO2 and SO2 in the elderly.^

Crystal size variations in Eemian-age ice from the GRIP ice core, Central Greenland

Continuous measurements of ice crystal size have been carried out on an 80 m sequence between 2790 and 2870 m depth in the GRIP ice core from Central Greenland. The ice in this interval is at present considered to orginate from the Eemian interglacial period. The record reveals that the crystal size in ice older than 100,000 yr is highly dependent on climatic conditions at the time of snowfall. This dependence shows up as a strong correlation between ?18O values and crystal size throughout the Eemian, as well as a negative correlation between crystal size and several soluble and insoluble impurities. Although high-resolution impurity records are available from selected parts of the Eemian ice, the study is not conclusive on which impurities are most effective in slowing grain growth. It is shown that the normal grain-growth process, commonly observed in the upper few hundred metres of polar ice sheets, does not yield grain sizes compatible with observed ones at this depth in the ice sheet, even in those parts of the Eemian ice where impurity drag effects are not present. Polygonization of crystals within the ice sheet and the nucleation and rapid growth of new grains at relatively high temperatures in the lowest part probably play an important role in producing the observed grain-size variations. The relevance of possible flow disturbances of the GRIP Eemian climatic record for the results presented is discussed briefly.