Estimates of hemodynamic response functions (HRF) are often integral parts of event-related fMRI analyses. Although HRFs vary across individuals and brain regions, few studies have investigated how variations affect the results of statistical analyses using the general linear model (GLM). In this study, we empirically estimated HRFs from primary motor and visual cortices and frontal and supplementary eye fields (SEF) in 20 subjects. We observed more variability across subjects than regions and correlated variation of time-to-peak values across several pairs of regions. Simulations examined the effects of observed variability on statistical results and ways different experimental designs and statistical models can limit these effects. Widely spaced and rapid event-related experimental designs with two sampling rates were tested. Statistical models compared an empirically derived HRF to a canonical HRF and included the first derivative of the HRF in the GLM. Small differences between the estimated and true HRFs did not cause false negatives, but larger differences within an observed range of variation, such as a 2.5-s time-to-onset misestimate, led to false negatives. Although small errors minimally affected detection of activity, time-to-onset misestimates as small as 1 s influenced model parameter estimation and therefore random effects analyses across subjects. Experiment and analysis design methods such as decreasing the sampling rate or including the HRF's temporal derivative in the GLM improved results, but did not eliminate errors caused by HRF misestimates. These results highlight the benefits of determining the best possible HRF estimate and potential negative consequences of assuming HRF consistency across subjects or brain regions.

AU-rich RNA-destabilizing elements (AREs) have become a paradigm for studying cytoplasmic mRNA turnover in mammalian cells. Though many RNA-binding proteins have been shown to bind to AREs in vitro, trans-acting factors that participate in the in vivo destabilization of cytoplasmic RNA by AREs remains unknown. Experiments were performed to investigate the cellular mechanisms and to identify potential trans-acting factors for ARE-directed mRNA decay. These experiments identified hnRNP D, a heterogeneous nuclear ribonucleoprotein (hnRNP) capable of shuttling between the nucleus and cytoplasm, as an RNA destabilizing protein in vivo in ARE-mediated rapid mRNA decay. Our results show that the ARE destabilizing function is dramatically impeded during hemin-induced erythroid differentiation and not in TPA-induced megakaryocytic differentiation of human erythroleukemic K562 cells. A sequestration of hnRNP D into a hemin-induced protein complex, termed hemin-regulated factor or HRF, correlates well with the loss of ARE-destabilizing function in the cytoplasm. Further experiments show that in hemin-treated cells, ectopic expression of hnRNP D restores the rapid decay directed by the ARE. The extent of destabilizing effect varies among the four isoforms of hnRNP D, with p37 and p42 displaying the most profound effect. These results demonstrate a specific cytoplasmic function for hnRNP D as an RNA-destabilizing protein in ARE-mediated decay pathway. These in vivo findings support an emerging idea that shuttling hnRNP proteins have not only a nuclear but also a cytoplasmic function in mRNA metabolism. The data further imply that shuttling hnRNP proteins define, at least in part, the nuclear history of individual mRNAs and thereby influence their cytoplasmic fate.

Epigenetic states and certain environmental responses in mammals and seed plants can persist in the next sexual generation. These transgenerational effects have potential adaptative significance as well as medical and agronomic ramifications. Recent evidence suggests that some abiotic and biotic stress responses of plants are transgenerational. For example, viral infection of tobacco plants and exposure of Arabidopsis thaliana plants to UVC and flagellin can induce transgenerational increases in homologous recombination frequency (HRF). Here we show that exposure of Arabidopsis plants to stresses, including salt, UVC, cold, heat and flood, resulted in a higher HRF, increased global genome methylation, and higher tolerance to stress in the untreated progeny. This transgenerational effect did not, however, persist in successive generations. Treatment of the progeny of stressed plants with 5-azacytidine was shown to decrease global genomic methylation and enhance stress tolerance. Dicer-like (DCL) 2 and DCL3 encode Dicer activities important for small RNA-dependent gene silencing. Stress-induced HRF and DNA methylation were impaired in dcl2 and dcl3 deficiency mutants, while in dcl2 mutants, only stress-induced stress tolerance was impaired. Our results are consistent with the hypothesis that stress-induced transgenerational responses in Arabidopsis depend on altered DNA methylation and smRNA silencing pathways.

Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.

An immunoglobulin E (IgE)-dependent histamine-releasing factor (HRF) produced by lymphocytes of atopic children and present in biological fluids of allergic patients has been identified and purified. Amino-terminal sequencing revealed extensive homology to a mouse protein, p21, and its human homolog, p23. Both recombinant proteins caused histamine release from the human basophils of a subpopulation of donors, and this release was dependent on IgE. Polyclonal antibodies recognized and removed the biological activity of recombinant and native HRF. HRF identifies a heterogeneity of IgE and is believed to play a prominent role in chronic allergic disease processes.

Absence seizures are 5-10 s episodes of impaired consciousness accompanied by 3-4 Hz generalized spike-and-wave discharge on electroencephalography (EEG). The time course of functional magnetic resonance imaging (fMRI) changes in absence seizures in relation to EEG and behavior is not known. We acquired simultaneous EEG-fMRI in 88 typical childhood absence seizures from nine pediatric patients. We investigated behavior concurrently using a continuous performance task or simpler repetitive tapping task. EEG time-frequency analysis revealed abrupt onset and end of 3-4 Hz spike-wave discharges with a mean duration of 6.6 s. Behavioral analysis also showed rapid onset and end of deficits associated with electrographic seizure start and end. In contrast, we observed small early fMRI increases in the orbital/medial frontal and medial/lateral parietal cortex >5 s before seizure onset, followed by profound fMRI decreases continuing >20 s after seizure end. This time course differed markedly from the hemodynamic response function (HRF) model used in conventional fMRI analysis, consisting of large increases beginning after electrical event onset, followed by small fMRI decreases. Other regions, such as the lateral frontal cortex, showed more balanced fMRI increases followed by approximately equal decreases. The thalamus showed delayed increases after seizure onset followed by small decreases, most closely resembling the HRF model. These findings reveal a complex and long-lasting sequence of fMRI changes in absence seizures, which are not detectable by conventional HRF modeling in many regions. These results may be important mechanistically for seizure initiation and termination and may also contribute to changes in EEG and behavior.

The brain is active even in the absence of explicit input or output as demonstrated from electrophysiological as well as imaging studies. Using a combined approach we measured spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal along with electroencephalography (EEG) in eleven healthy subjects during relaxed wakefulness (eyes closed). In contrast to other studies which used the EEG frequency information to guide the functional MRI (fMRI) analysis, we opted for transient EEG events, which identify and quantify brain electric microstates as time epochs with quasi-stable field topography. We then used this microstate information as regressors for the BOLD fluctuations. Single trial EEGs were segmented with a specific module of the LORETA (low resolution electromagnetic tomography) software package in which microstates are represented as normalized vectors constituted by scalp electric potentials, i.e., the related 3-dimensional distribution of cortical current density in the brain. Using the occurrence and the duration of each microstate, we modeled the hemodynamic response function (HRF) which revealed BOLD activation in all subjects. The BOLD activation patterns resembled well known resting-state networks (RSNs) such as the default mode network. Furthermore we "cross validated" the data performing a BOLD independent component analysis (ICA) and computing the correlation between each ICs and the EEG microstates across all subjects. This study shows for the first time that the information contained within EEG microstates on a millisecond timescale is able to elicit BOLD activation patterns consistent with well known RSNs, opening new avenues for multimodal imaging data processing.

In neuroimaging research on attention, cognitive control, decision-making, and other areas where response time (RT) is a critical variable, the temporal variability associated with the decision is often assumed to be inconsequential to the hemodynamic response (HDR) in rapid event-related designs. On this basis, the majority of published studies model brain activity lasting less than 4 s with brief impulses representing the onset of neural or cognitive events, which are then convolved with the hemodynamic impulse response function (HRF). However, electrophysiological studies have shown that decision-related neuronal activity is not instantaneous, but in fact, often lasts until the motor response. It is therefore possible that small differences in neural processing durations, similar to human RTs, will produce noticeable changes in the HDR, and therefore in the results of regression analyses. In this study we compare the effectiveness of traditional models that assume no temporal variance with a model that explicitly accounts for the duration of very brief epochs of neural activity. Using both simulations and fMRI data, we show that brief differences in duration are detectable, making it possible to dissociate the effects of stimulus intensity from stimulus duration, and that optimizing the model for the type of activity being detected improves the statistical power, consistency, and interpretability of results.

Partial least squares (PLS) has proven to be a important multivariate analytic tool for positron emission tomographic and, more recently, event-related potential (ERP) data. The application to ERP incorporates the ability to analyze space and time together, a feature that has obvious appeal for event-related functional magnetic resonance imaging (fMRI) data. This paper presents the extension of spatiotemporal PLS (ST-PLS) to fMRI, explaining the theoretical foundation and application to an fMRI study of auditory and visual perceptual memory. Analysis of activation effects with ST-PLS was compared with conventional univariate random effects analysis, showing general consensus for both methods, but several unique observations by ST-PLS, including enhanced statistical power. The application of ST-PLS for assessment of task-dependent brain-behavior relationships is also presented. Singular features of ST-PLS include (1) no assumptions about the shape of the hemodynamic response functions (HRFs); (2) robust statistical assessment at the image level through permutation tests; (3) protection against outlier influences at the voxel level through bootstrap resampling; (4) flexible analytic configurations that allow assessment of activation difference, brain-behavior relations, and functional connectivity. These features enable ST-PLS to act as an important complement to other multivariate and univariate approaches used in neuroimaging research.

The intra-class class correlation coefficient (ICC) is a prominent statistic to measure test-retest reliability of fMRI data. It can be used to address the question of whether regions of high group activation in a first scan session will show preserved subject differentiability in a second session. With this purpose, we present a method that extends voxel-wise ICC analysis. We show that voxels with high group activation have more probability of being reliable, if a subsequent session is performed, than typical voxels across the brain or across white matter. We also find that the existence of some voxels with high ICC but low group activation can be explained by stable signals across sessions that poorly fit the HRF model. At a region of interest level, we show that our voxel-wise ICC calculation is more robust than previous implementations under variations of smoothing and cluster size. The method also allows formal comparisons between the reliabilities of given brain regions; aimed at establishing which ROIs discriminate best between individuals. The method is applied to an auditory and a verbal working memory task. A reliability toolbox for SPM5 is provided at http://brainmap.co.uk.

BACKGROUND

Active travel to school (ATS) has been identified as an important source of physical activity for youth. However, the relationship between ATS and health-related fitness (HRF) among youth remains unclear.

METHODS

A systematic search of seven electronic databases (EMBASE, OVID MEDLINE, PsycINFO, PubMed, Scopus, SPORTDiscus and TRIS on line) was conducted in December 2009 and studies published since 1980 were considered for inclusion.

RESULTS

Twenty seven articles were identified that explored the relationship between ATS and the following aspects of HRF: weight status/body composition, cardiorespiratory fitness, muscular fitness and flexibility. Forty-eight percent of the studies that examined the relationship between ATS and weight status/body composition reported significant associations, this increased to 55% once poor quality studies were removed. Furthermore, the findings from five studies, including one longitudinal study, indicate that ATS is positively associated with cardiorespiratory fitness in youth. However, the evidence for the relationships between ATS and muscular fitness or flexibility is equivocal and limited by low study numbers.

CONCLUSIONS

There is some evidence to suggest that ATS is associated with a healthier body composition and level of cardiorespiratory fitness among youth. Strategies to increase ATS are warranted and should be included in whole-of-school approaches to the promotion of physical activity.

BACKGROUND

The mechanisms underlying progressive renal fibrosis are unknown, but the common association of fibrosis and microvascular loss suggests that hypoxia per se may be a fibrogenic stimulus.

METHODS

To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointerstitium, possess oxygen-sensitive responses relevant to fibrogenesis, cells were exposed to 1% O2 in vitro.

RESULTS

Hypoxia simultaneously stimulated extracellular matrix synthesis and suppressed turnover with increased production of collagen alpha1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase (TIMP)-1. These effects are time dependent, require new RNA and protein synthesis, and are specific to hypoxia. The changes in Coll-I and TIMP-1 gene expression involve a heme-protein O2 sensor and protein kinase- and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-beta1 (TGF-beta1), neutralizing anti-TGF-beta1-antibody did not block hypoxia-induced Coll-I and TIMP-1 mRNA expression. Furthermore, hypoxic-cell conditioned-medium had no effect on the expression of these mRNAs in naive fibroblasts, suggesting direct effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 promoter and demonstrated HIF-1-dependent promoter activation by decreased ambient pO2.

CONCLUSIONS

These data suggest that hypoxia co-ordinately up-regulates matrix production and decreases turnover in renal fibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypoxic effects on the expression of genes involved in fibrogenesis.

Erythrocytes are poorly lysed by homologous complement, whereas they are readily lysed by heterologous complement. This phenomenon had been attributed to an interference by the cell surface with the action of complement components C8 and C9. To isolate the responsible membrane constituent, detergent-solubilized human erythrocyte (EH) membranes were subjected to affinity chromatography by using human C9-Sepharose. The isolated protein had a mass of 38 kDa and, incorporated into liposomes, was highly effective in inhibiting complement-mediated channel expression, including the C5b-8, membrane attack complex, and tubular polymer of C9 channels. Antibody produced to the 38-kDa protein caused a 20-fold increase in reactive lysis of EH by isolated C5b6, C7, C8, and C9. The antibody did not enhance C5b-7 uptake, but it affected C9 binding to the target cell membrane. Antibody to human decay-accelerating factor, used as a control, had no effect on reactive lysis of EH. Anti-38-kDa protein did not enhance the action on EH of C8 and C9 from other species, indicating that the action of this regulatory protein is species specific. It was therefore termed homologous restriction factor (HRF). Blood cells other than erythrocytes, such as polymorphonuclear leukocytes, also exhibited cell-surface HRF activity. In immunoblots of freshly isolated EH membranes, anti-38-kDa HRF detected primarily a 65-kDa protein, suggesting that the 38-kDa protein constitutes an active fragment of membrane HRF. Because of the specific binding reaction observed between HRF and C8 or C9, HRF was tested with anti-human C8 and anti-human C9. A limited immunochemical relationship of HRF to C8 and C9 could be established and solid-phase anti-C9 proved an efficient tool for the isolation of HRF from solubilized EH membranes.

In this work, we investigated the effect of the regional variability of the hemodynamic response on the sensitivity of Granger causality (GC) analysis of functional magnetic resonance imaging (fMRI) data to neuronal causal influences. We simulated fMRI data by convolving a standard canonical hemodynamic response function (HRF) with local field potentials (LFPs) acquired from the macaque cortex and manipulated the causal influence and neuronal delays between the LFPs, the hemodynamic delays between the HRFs, the signal-to-noise ratio (SNR), and the sampling period (TR) to assess the effect of each of these factors on the detectability of the neuronal delays from GC analysis of fMRI. In our first bivariate implementation, we assumed the worst-case scenario of the hemodynamic delay being at the empirical upper limit of its normal physiological range and opposing the direction of neuronal delay. We found that, in the absence of HRF confounds, even tens of milliseconds of neuronal delays can be inferred from fMRI. However, in the presence of HRF delays which opposed neuronal delays, the minimum detectable neuronal delay was hundreds of milliseconds. In our second multivariate simulation, we mimicked the real situation more closely by using a multivariate network of four time series and assumed the hemodynamic and neuronal delays to be unknown and drawn from a uniform random distribution. The resulting accuracy of detecting the correct multivariate network from fMRI was well above chance and was up to 90% with faster sampling. Generically, under all conditions, faster sampling and low measurement noise improved the sensitivity of GC analysis of fMRI data to neuronal causality.

Near-Infrared Spectroscopy (NIRS) allows the recovery of cortical oxy- and deoxyhemoglobin changes associated with evoked brain activity. NIRS is a back-reflection measurement making it very sensitive to the superficial layers of the head, i.e. the skin and the skull, where systemic interference occurs. As a result, the NIRS signal is strongly contaminated with systemic interference of superficial origin. A recent approach to overcome this problem has been the use of additional short source-detector separation optodes as regressors. Since these additional measurements are mainly sensitive to superficial layers in adult humans, they can be used to remove the systemic interference present in longer separation measurements, improving the recovery of the cortical hemodynamic response function (HRF). One question that remains to answer is whether or not a short separation measurement is required in close proximity to each long separation NIRS channel. Here, we show that the systemic interference occurring in the superficial layers of the human head is inhomogeneous across the surface of the scalp. As a result, the improvement obtained by using a short separation optode decreases as the relative distance between the short and the long measurement is increased. NIRS data was acquired on 6 human subjects both at rest and during a motor task consisting of finger tapping. The effect of distance between the short and the long channel was first quantified by recovering a synthetic hemodynamic response added over the resting-state data. The effect was also observed in the functional data collected during the finger tapping task. Together, these results suggest that the short separation measurement must be located as close as 1.5 cm from the standard NIRS channel in order to provide an improvement which is of practical use. In this case, the improvement in Contrast-to-Noise Ratio (CNR) compared to a standard General Linear Model (GLM) procedure without using any small separation optode reached 50% for HbO and 100% for HbR. Using small separations located farther than 2 cm away resulted in mild or negligible improvements only.

Transcription factors of the bHLH-PAS protein family are important regulators of developmental processes such as neurogenesis and tracheal development in invertebrates. Recently a bHLH-PAS protein, named trachealess (trl) was identified as a master regulator of tracheogenesis. Hypoxia-inducible factor, HIF-1 alpha, is a vertebrate relative of trl which is likely to be involved in growth of blood vessels by the induction of vascular endothelial growth factor (VEGF) in response to hypoxia. In the present study we describe mRNA cloning and mRNA expression pattern of mouse HIF-related factor (HRF), a novel close relative of HIF-1 alpha which is expressed most prominently in brain capillary endothelial cells and other blood vessels as well as in bronchial epithelium in the embryo and the adult. In addition, smooth muscle cells of the uterus, neurons, brown adipose tissue and various epithelial tissues express HRF mRNA as well. High expression levels of HRF mRNA in embryonic choroid plexus and kidney glomeruli, places where VEGF is highly expressed, suggest a role of this factor in VEGF gene activation similar to that of HIF-1 alpha. Given the similarity between morphogenesis of the tracheal system and the vertebrate vascular system, the expression pattern of HRF in the vasculature and the bronchial tree raises the possibility that this family of transcription factors may be involved in tubulogenesis.

Near-infrared spectroscopy (NIRS) is susceptible to signal artifacts caused by relative motion between NIRS optical fibers and the scalp. These artifacts can be very damaging to the utility of functional NIRS, particularly in challenging subject groups where motion can be unavoidable. A number of approaches to the removal of motion artifacts from NIRS data have been suggested. In this paper we systematically compare the utility of a variety of published NIRS motion correction techniques using a simulated functional activation signal added to 20 real NIRS datasets which contain motion artifacts. Principle component analysis, spline interpolation, wavelet analysis, and Kalman filtering approaches are compared to one another and to standard approaches using the accuracy of the recovered, simulated hemodynamic response function (HRF). Each of the four motion correction techniques we tested yields a significant reduction in the mean-squared error (MSE) and significant increase in the contrast-to-noise ratio (CNR) of the recovered HRF when compared to no correction and compared to a process of rejecting motion-contaminated trials. Spline interpolation produces the largest average reduction in MSE (55%) while wavelet analysis produces the highest average increase in CNR (39%). On the basis of this analysis, we recommend the routine application of motion correction techniques (particularly spline interpolation or wavelet analysis) to minimize the impact of motion artifacts on functional NIRS data.

FMRI modelling requires flexible haemodynamic response function (HRF) modelling, with the HRF being allowed to vary spatially and between subjects. To achieve this flexibility, voxelwise parameterised HRFs have been proposed; however, inference on such models is very slow. An alternative approach is to use basis functions allowing inference to proceed in the more manageable General Linear Model (GLM) framework. However, a large amount of the subspace spanned by the basis functions produces nonsensical HRF shapes. In this work we propose a technique for choosing a basis set, and then the means to constrain the subspace spanned by the basis set to only include sensible HRF shapes. Penny et al. showed how Variational Bayes can be used to infer on the GLM for FMRI. Here we extend the work of Penny et al. to give inference on the GLM with constrained HRF basis functions and with spatial Markov Random Fields on the autoregressive noise parameters. Constraining the subspace spanned by the basis set allows for far superior separation of activating voxels from nonactivating voxels in FMRI data. We use spatial mixture modelling to produce final probabilities of activation and demonstrate increased sensitivity on an FMRI dataset.

To determine frequency of methicillin-resistant Staphylococcus aureus infections caused by strains typically associated with community-acquired infections (USA300) among persons with healthcare-related risk factors (HRFs), we evaluated surveillance data. Of patients with HRFs, 18%-28% had a "community-associated" strain, primarily USA300; of patients without HRFs, 26% had a "healthcare-associated" strain, typically USA100.

Hypoxic stress plays a role in pathophysiologic states such as myocardial infarction and cerebral vascular events as well as in normal physiologic conditions including development and hematopoiesis. Members of the hypoxia inducible factor (HIF) family function as transcriptional regulators of genes involved in the hypoxic response. After generating adult mice that globally lack endothelial PAS domain protein 1 (EPAS1, also known as HIF-2alpha/HRF/HLF/MOP3), the second member of the HIF family, characterization of the hematopoietic cell population indicated that the loss of EPAS1/HIF-2alpha resulted in pancytopenia. Using bone marrow reconstitution experiments of lethally irradiated hosts, we have defined the extent and site of hematopoietic impairment in the EPAS1/HIF-2alpha null mice. These data suggest a critical role for EPAS1/HIF-2alpha in maintaining a functional microenvironment in the bone marrow for effective hematopoiesis.

Women who pass menopause face many changes that may lead to loss of health-related fitness (HRF), especially if sedentary. Many exercise recommendations are also relevant for early postmenopausal women; however, these may not meet their specific needs because the recommendations are based mainly on studies on men. We conducted a systematic review for randomised, controlled exercise trials on postmenopausal women (aged 50 to 65 years) on components of HRF. HRF consists of morphological fitness (body composition and bone strength), musculoskeletal fitness (muscle strength and endurance, flexibility), motor fitness (postural control), cardiorespiratory fitness (maximal aerobic power, blood pressure) and metabolic fitness (lipid and carbohydrate metabolism). The outcome variables chosen were: bodyweight; proportion of body fat of total bodyweight (F%); bone mineral density (BMD); bone mineral content (BMC); various tests on muscle performance, flexibility, balance and coordination; maximal oxygen consumption (V-dotO(2max)); resting blood pressure (BP); total cholesterol (TC); high-density lipoprotein-cholesterol; low-density lipoprotein-cholesterol; triglycerides; blood glucose and insulin. The feasibility of the exercise programme was assessed from drop-out, attendance and injury rates. Twenty-eight randomised controlled trials with 2646 participants were assessed. In total, 18 studies reported on the effects of exercise on bodyweight and F%, 16 on BMD or BMC, 11 on muscular strength or endurance, five on flexibility, six on balance or coordination, 18 on V-dotO(2max), seven on BP, nine on lipids and two studies on glucose an one on insulin. Based on these studies, early postmenopausal women could benefit from 30 minutes of daily moderate walking in one to three bouts combined with a resistance training programme twice a week. For a sedentary person, walking is feasible and can be incorporated into everyday life. A feasible way to start resistance training is to perform eight to ten repetitions of eight to ten exercises for major muscle groups starting with 40% of one repetition maximum. Resistance training initially requires professional instruction, but can thereafter be performed at home with little or no equipment as an alternative for a gym with weight machines. Warm-up and cool-down with stretching should be a part of every exercise session. The training described above is likely to preserve normal bodyweight, or combined with a weight-reducing diet, preserve BMD and increase muscle strength. Based on limited evidence, such exercise might also improve flexibility, balance and coordination, decrease hypertension and improve dyslipidaemia.

Combined EEG-fMRI has recently been used to explore the BOLD responses to interictal epileptiform discharges. This study examines whether misspecification of the form of the haemodynamic response function (HRF) results in significant fMRI responses being missed in the statistical analysis. EEG-fMRI data from 31 patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec after each interictal event, in addition to a standard HRF that peaked after 5.4 sec. In four patients, fMRI responses were correlated with gadolinium-enhanced MR angiograms and with EEG data from intracranial electrodes. In an attempt to understand the absence of BOLD responses in a significant group of patients, the degree of signal loss occurring as a result of magnetic field inhomogeneities was compared with the detected fMRI responses in ten patients with temporal lobe spikes. Using multiple HRFs resulted in an increased percentage of data sets with significant fMRI activations, from 45% when using the standard HRF alone, to 62.5%. The standard HRF was good at detecting positive BOLD responses, but less appropriate for negative BOLD responses, the majority of which were more accurately modelled by an HRF that peaked later than the standard. Co-registration of statistical maps with gadolinium-enhanced MRIs suggested that the detected fMRI responses were not in general related to large veins. Signal loss in the temporal lobes seemed to be an important factor in 7 of 12 patients who did not show fMRI activations with any of the HRFs.

EEG was recorded during fMRI scanning of 16 normal controls in resting condition with eyes closed. Time variations of the occipital alpha band amplitudes were correlated to the fMRI signal variations to obtain insight into the hemodynamic correlates of the EEG alpha activity. Contrary to earlier studies, no a priori assumptions were made on the expected shape of the alpha band response function (ARF). The ARF of different brain regions and subjects were explored and compared. It was found that: (1) the ARF of the thalamus is mainly positive. (2) The ARFs at the occipital and left and right parietal points are similar in amplitude and timing. (3) The peak time of the thalamus is a few seconds earlier than that of occipital and parietal cortex. (4) No systematic BOLD activity was found preceding the alpha band activity, although in the two subjects with the strongest alpha band power such correlation was present. (5) There is a strong and immediate positive correlation at the eyeball, and a strong negative correlation at the back of the eye. Furthermore, it was found that in one subject the cortical ARF was positive, contrary to the other subjects. Finally, a cluster analysis of the observed ARF, in combination with a Modulated Sine Model (MSM) fit to the estimated ARF, revealed that within the cortex the ARF peak time shows a spatial pattern that may be interpreted as a traveling wave. The spatial pattern of alpha band response function represents the combined effect of local differences in electrical alpha band activity and local differences in the hemodynamic response function (HRF) onto these electrical activities. To disentangle the contributions of both factors, more advanced integration of EEG inverse modeling and hemodynamic response modeling is required in future studies.

We present a fully Bayesian approach to modeling in functional magnetic resonance imaging (FMRI), incorporating spatio-temporal noise modeling and haemodynamic response function (HRF) modeling. A fully Bayesian approach allows for the uncertainties in the noise and signal modeling to be incorporated together to provide full posterior distributions of the HRF parameters. The noise modeling is achieved via a nonseparable space-time vector autoregressive process. Previous FMRI noise models have either been purely temporal, separable or modeling deterministic trends. The specific form of the noise process is determined using model selection techniques. Notably, this results in the need for a spatially nonstationary and temporally stationary spatial component. Within the same full model, we also investigate the variation of the HRF in different areas of the activation, and for different experimental stimuli. We propose a novel HRF model made up of half-cosines, which allows distinct combinations of parameters to represent characteristics of interest. In addition, to adaptively avoid over-fitting we propose the use of automatic relevance determination priors to force certain parameters in the model to zero with high precision if there is no evidence to support them in the data. We apply the model to three datasets and observe matter-type dependence of the spatial and temporal noise, and a negative correlation between activation height and HRF time to main peak (although we suggest that this apparent correlation may be due to a number of different effects).