Reliability of Task-Based fMRI for Preoperative Planning: A Test-Retest Study in Brain Tumor Patients and Healthy Controls

Background

Functional magnetic resonance imaging (fMRI) continues to develop as a clinical tool for patients with brain cancer, offering data that may directly influence surgical decisions. Unfortunately, routine integration of preoperative fMRI has been limited by concerns about reliability. Many pertinent studies have been undertaken involving healthy controls, but work involving brain tumor patients has been limited. To develop fMRI fully as a clinical tool, it will be critical to examine these reliability issues among patients with brain tumors. The present work is the first to extensively characterize differences in activation map quality between brain tumor patients and healthy controls, including the effects of tumor grade and the chosen behavioral testing paradigm on reliability outcomes.

Method

Test-retest data were collected for a group of low-grade (n = 6) and high-grade glioma (n = 6) patients, and for matched healthy controls (n = 12), who performed motor and language tasks during a single fMRI session. Reliability was characterized by the spatial overlap and displacement of brain activity clusters, BOLD signal stability, and the laterality index. Significance testing was performed to assess differences in reliability between the patients and controls, and low-grade and high-grade patients; as well as between different fMRI testing paradigms.

Results

There were few significant differences in fMRI reliability measures between patients and controls. Reliability was significantly lower when comparing high-grade tumor patients to controls, or to low-grade tumor patients. The motor task produced more reliable activation patterns than the language tasks, as did the rhyming task in comparison to the phonemic fluency task.

Conclusion

In low-grade glioma patients, fMRI data are as reliable as healthy control subjects. For high-grade glioma patients, further investigation is required to determine the underlying causes of reduced reliability. To maximize reliability outcomes, testing paradigms should be carefully selected to generate robust activation patterns.     

健康妇女阴道乳酸杆菌定性与定量研究

本文运用微生态学研究方法,对健康妇女阴道乳酸杆菌的分布情况进行调查。结果表明:健康妇女阴道乳酸杆菌的分离率75.44％,平均活菌数均值(log10~n±SD)7.2810±1.1618。常见的阴道乳酸杆菌种的分离率及活菌对数值为:嗜酸乳杆菌(33.3％,7.6883±1.4076),唾液乳杆菌(10.53％,6.4949±1.4254),乳酸乳杆菌(8.8％,8.0687±1.7102),德氏乳杆菌(7.0％,8.1134±0.6311),赖氏乳杆菌(7.0％,7.3349±0.9052)。揭示这几种乳杆菌可能是健康妇女阴道乳酸杆菌属的重要成员,其生理学意义及种类、数量变化的临床意义,值得进一步研究。     

Relationships between Platelets and Blood Cells in Postprandial Glycemia in Healthy Individuals

The relationships between platelet aggregation and blood cell amount were studied in healthy subjects after fasting and after a standard carbohydrate breakfast. Positive relationships were revealed between certain parameters of platelet aggregation and the amounts of monocytes and eosinophils. Negative relationships were revealed between most parameters of platelet aggregation and the amount of platelets. Along with the well-known food leukocytosis and increased fibrinogen, postprandial conditions were characterized by an increase in certain parameters of platelet aggregation, destruction of the relationship between the fibrinogen concentration and platelet aggregation, impairment of the inverse relationship between the amount and aggregation of platelets, and moderate direct or inverse relationships between certain parameters of the first and the second stages of platelet aggregation and the erythrocyte parameters. As a disturbing factor, postprandial conditions activated platelet hemostasis by modulating the initial stages of aggregation and substantially changed the interrelations between blood cells.     

Transient Responses to Rapid Changes in Mean and Variance in Spiking Models

The mean input and variance of the total synaptic input to a neuron can vary independently, suggesting two distinct information channels. Here we examine the impact of rapidly varying signals, delivered via these two information conduits, on the temporal dynamics of neuronal firing rate responses. We examine the responses of model neurons to step functions in either the mean or the variance of the input current. Our results show that the temporal dynamics governing response onset depends on the choice of model. Specifically, the existence of a hard threshold introduces an instantaneous component into the response onset of a leaky-integrate-and-fire model that is not present in other models studied here. Other response features, for example a decaying oscillatory approach to a new steady-state firing rate, appear to be more universal among neuronal models. The decay time constant of this approach is a power-law function of noise magnitude over a wide range of input parameters. Understanding how specific model properties underlie these response features is important for understanding how neurons will respond to rapidly varying signals, as the temporal dynamics of the response onset and response decay to new steady-state determine what range of signal frequencies a population of neurons can respond to and faithfully encode.     

Extensive Pollen Flow but Few Pollen Donors and High Reproductive Variance in an Extremely Fragmented Landscape

Analysing pollen movement is a key to understanding the reproductive system of plant species and how it is influenced by the spatial distribution of potential mating partners in fragmented populations. Here we infer parameters related to levels of pollen movement and diversity of the effective pollen cloud for the wind-pollinated shrub Pistacia lentiscus across a highly disturbed landscape using microsatellite loci. Paternity analysis and the indirect KinDist and Mixed Effect Mating models were used to assess mating patterns, the pollen dispersal kernel, the effective number of males (N_ep) and their relative individual fertility, as well as the existence of fine-scale spatial genetic structure in adult plants. All methods showed extensive pollen movement, with high rates of pollen flow from outside the study site (up to 73–93%), fat-tailed dispersal kernels and large average pollination distances (δ = 229–412 m). However, they also agreed in detecting very few pollen donors (N_ep = 4.3–10.2) and a large variance in their reproductive success: 70% of males did not sire any offspring among the studied female plants and 5.5% of males were responsible for 50% of pollinations. Although we did not find reduced levels of genetic diversity, the adult population showed high levels of biparental inbreeding (14%) and strong spatial genetic structure (S_p = 0.012), probably due to restricted seed dispersal and scarce safe sites for recruitment. Overall, limited seed dispersal and the scarcity of successful pollen donors can be contributing to generate local pedigrees and to increase inbreeding, the prelude of genetic impoverishment.     

Developmental Trajectories of Amygdala and Hippocampus from Infancy to Early Adulthood in Healthy Individuals

Knowledge of amygdalar and hippocampal development as they pertain to sex differences and laterality would help to understand not only brain development but also the relationship between brain volume and brain functions. However, few studies investigated development of these two regions, especially during infancy. The purpose of this study was to examine typical volumetric trajectories of amygdala and hippocampus from infancy to early adulthood by predicting sexual dimorphism and laterality. We performed a cross-sectional morphometric MRI study of amygdalar and hippocampal growth from 1 month to 25 years old, using 109 healthy individuals. The findings indicated significant non-linear age-related volume changes, especially during the first few years of life, in both the amygdala and hippocampus regardless of sex. The peak ages of amygdalar and hippocampal volumes came at the timing of preadolescence (9–11 years old). The female amygdala reached its peak age about one year and a half earlier than the male amygdala did. In addition, its rate of growth change decreased earlier in the females. Furthermore, both females and males displayed rightward laterality in the hippocampus, but only the males in the amygdala. The robust growth of the amygdala and hippocampus during infancy highlight the importance of this period for neural and functional development. The sex differences and laterality during development of these two regions suggest that sex-related factors such as sex hormones and functional laterality might affect brain development.     

A Method to Prioritize Quantitative Traits and Individuals for Sequencing in Family-Based Studies

Owing to recent advances in DNA sequencing, it is now technically feasible to evaluate the contribution of rare variation to complex traits and diseases. However, it is still cost prohibitive to sequence the whole genome (or exome) of all individuals in each study. For quantitative traits, one strategy to reduce cost is to sequence individuals in the tails of the trait distribution. However, the next challenge becomes how to prioritize traits and individuals for sequencing since individuals are often characterized for dozens of medically relevant traits. In this article, we describe a new method, the Rare Variant Kinship Test (RVKT), which leverages relationship information in family-based studies to identify quantitative traits that are likely influenced by rare variants. Conditional on nuclear families and extended pedigrees, we evaluate the power of the RVKT via simulation. Not unexpectedly, the power of our method depends strongly on effect size, and to a lesser extent, on the frequency of the rare variant and the number and type of relationships in the sample. As an illustration, we also apply our method to data from two genetic studies in the Old Order Amish, a founder population with extensive genealogical records. Remarkably, we implicate the presence of a rare variant that lowers fasting triglyceride levels in the Heredity and Phenotype Intervention (HAPI) Heart study (p = 0.044), consistent with the presence of a previously identified null mutation in the APOC3 gene that lowers fasting triglyceride levels in HAPI Heart study participants.     

Quantitative and Qualitative Approaches to Identifying Migration Chronology in a Continental Migrant

The degree to which extrinsic factors influence migration chronology in North American waterfowl has not been quantified, particularly for dabbling ducks. Previous studies have examined waterfowl migration using various methods, however, quantitative approaches to define avian migration chronology over broad spatio-temporal scales are limited, and the implications for using different approaches have not been assessed. We used movement data from 19 female adult mallards (Anas platyrhynchos) equipped with solar-powered global positioning system satellite transmitters to evaluate two individual level approaches for quantifying migration chronology. The first approach defined migration based on individual movements among geopolitical boundaries (state, provincial, international), whereas the second method modeled net displacement as a function of time using nonlinear models. Differences in migration chronologies identified by each of the approaches were examined with analysis of variance. The geopolitical method identified mean autumn migration midpoints at 15 November 2010 and 13 November 2011, whereas the net displacement method identified midpoints at 15 November 2010 and 14 November 2011. The mean midpoints for spring migration were 3 April 2011 and 20 March 2012 using the geopolitical method and 31 March 2011 and 22 March 2012 using the net displacement method. The duration, initiation date, midpoint, and termination date for both autumn and spring migration did not differ between the two individual level approaches. Although we did not detect differences in migration parameters between the different approaches, the net displacement metric offers broad potential to address questions in movement ecology for migrating species. Ultimately, an objective definition of migration chronology will allow researchers to obtain a comprehensive understanding of the extrinsic factors that drive migration at the individual and population levels. As a result, targeted conservation plans can be developed to support planning for habitat management and evaluation of long-term climate effects.     

Metabolomics Reveals Metabolically Healthy and Unhealthy Obese Individuals Differ in their Response to a Caloric Challenge

Objective

To determine if metabolically healthy obese (MHO) individuals have a different metabolic response to a standardized diet compared to lean healthy (LH) and metabolically unhealthy obese (MUO) individuals.

Methods

Thirty adults (35–70 yrs) were classified as LH, MHO, and MUO according to anthropometric and clinical measurements. Participants consumed a standardized high calorie meal (~1330 kcal). Blood glucose and insulin were measured at fasting, and 15, 30, 60, 90 and 120 min postprandially. Additional blood samples were collected for the targeted analysis of amino acids (AAs) and derivatives, and fatty acids (FAs).

Results

The postprandial response (i.e., area under the curve, AUC) for serum glucose and insulin were similar between MHO and LH individuals, and significantly lower than MUO individuals (p < 0.05). Minor differences were found in postprandial responses for AAs between MHO and MUO individuals, while three polyunsaturated FAs (linoleic acid, γ-linolenic acid, arachidonic acid) showed smaller changes in serum after the meal in MHO individuals compared to MUO. Fasting levels for various AAs (notably branched-chain AA) and FAs (e.g., saturated myristic and palmitic acids) were found to correlate with glucose and insulin AUC.

Conclusion

MHO individuals show preserved insulin sensitivity and a greater ability to adapt to a caloric challenge compared to MUO individuals.     

A Higher Number of TMS-Elicited MEP from a Combined Hotspot Improves Intra- and Inter-Session Reliability of the Upper Limb Muscles in Healthy Individuals

We aimed to determine, using transcranial magnetic stimulation (TMS), the number of elicited motor evoked potentials (MEPs) that induces the highest intra- and inter-sessions reliability for the extensor carpi radialis (ECR) and first dorsal interosseus (FDI) muscles. Twelve healthy subjects participated in this study on two separate days. Single pulse magnetic stimuli were triggered with Magstim 200² to obtain MEPs from the muscles of interest, with the subjects in a relaxed position. Reliability of MEP responses was investigated in three blocks of 5, 10 and 15 trials. The intra- and inter-session reliability of the MEPs'' amplitudes and latencies were assessed using intraclass correlation coefficients (ICCs). Repeated measures ANOVA and paired t-tests revealed no significant time effect in the MEP amplitude and latency measurements (P>0.05). The ICCs indicated high intra-session reliability in the MEPs'' amplitudes for the ECR and FDI muscles (0.77 to 0.99, 0.90 to 0.99, respectively) and latency (0.80 to 1.00, 0.75 to 0.97, respectively). The MEPs'' amplitudes also had high inter-session reliability (0.84 to 0.97, 0.88 to 0.93, respectively), as did their latency (0.80 to 0.90, 0.75 to 0.97, respectively). Highest intra- and inter-session reliability was achieved for blocks of 10 and 15 trials. Our data suggest that intra- and inter-session comparisons should be performed using at least 10 MEPs in “combined hotspot” stimulation technique to ensure highest reliability.     

Comparative Analysis of Physio-Biochemical Responses to Cold Stress in Tetraploid and Hexaploid Wheat

The cellular changes induced by cold stress (CS) include responses that lead to oxidative stress and limits plant growth, metabolism, and productivity. In this study, responses of physio-biochemical to CS phases were comparatively studied in three genotypes of bread and durum wheats differing in sensitivity, two of them (Norstar, bread wheat and Gerdish, durum wheat) were tolerant to CS and the other one, SRN (durum wheat) was sensitive to CS. 14-day-old seedlings were subjected to CS (12 and 24 h) with or without cold acclimation (CA) phase. During CS, the elevated levels of electrolyte leakage index, contents of hydrogen peroxide (H₂O₂), and malondialdehyde in Norstar and Gerdish were lower than that of SRN plants. Positive correlation and co-regulation of reactive oxygen species (ROS) scavenging systems, superoxide dismutase, catalase, ascorbate peroxidase, guaiacol peroxidase, and proline especially after CA phase suggested crucial role for holding back toxic ROS levels in CS phase. However, different activities of this system resulted in different intensities of oxidative stress in acclimated and non-acclimated plants. Our results showed that a CA phase induced oxidative stress tolerance by modulating antioxidative systems. These responses confirmed the existence of wide range of genetic capacity in durum wheat to increase cold tolerance particularly in Gerdish so that the sensitivity of SRN plants to CS was linearly correlated with the more decrease of antioxidant systems. These general responses may be a sign for associating other metabolites or enzymes activities to create partly tolerance against cold-induced oxidative stress. Eventually, assessing the dynamic of cell responses in short intervals after CS without CA phases profitably could be a novel path in plant stress response investigations in a short period of time.     

Cardiovascular Responses to Isometric Muscle Tension in Healthy Subjects and in Patients with Neurocirculatory Dystonia

Cardiovascular responses to isometric tensions of small and large muscle groups under loads at 10, 20, or 30% of the maximum voluntary strength were studied in healthy female students and in their counterparts with neurocirculatory dystonia. It was found that the systolic and diastolic arterial pressure can either increase or decrease in response to these loads (pressor or depressor effects, respectively).     

A Quantitative Method to Track Protein Translocation between Intracellular Compartments in Real-Time in Live Cells Using Weighted Local Variance Image Analysis

The genetic expression of cloned fluorescent proteins coupled to time-lapse fluorescence microscopy has opened the door to the direct visualization of a wide range of molecular interactions in living cells. In particular, the dynamic translocation of proteins can now be explored in real time at the single-cell level. Here we propose a reliable, easy-to-implement, quantitative image processing method to assess protein translocation in living cells based on the computation of spatial variance maps of time-lapse images. The method is first illustrated and validated on simulated images of a fluorescently-labeled protein translocating from mitochondria to cytoplasm, and then applied to experimental data obtained with fluorescently-labeled hexokinase 2 in different cell types imaged by regular or confocal microscopy. The method was found to be robust with respect to cell morphology changes and mitochondrial dynamics (fusion, fission, movement) during the time-lapse imaging. Its ease of implementation should facilitate its application to a broad spectrum of time-lapse imaging studies.     

CD16 Expression on Monocytes in Healthy Individuals but Not Schistosome-Infected Patients Is Positively Associated with Levels of Parasite-Specific IgG and IgG1

Human IgG1 antibody responses are associated with protection against Schistosoma haematobium infection and are now a target for schistosome vaccine development. This study aimed to investigate the relationship between total IgG and the IgG subclasses and the monocyte IgG receptor, known as FcγRIIIa or CD16, in schistosome exposed people. Systemic levels of schistosome-specific anti-adult worm total IgG and IgG subclass titres were measured by ELISA in 100 individuals from an S. haematobium endemic area in Zimbabwe and, using parametric statistical methods and regression analysis, related to the levels of CD16 expression on individuals'' circulating monocytes, determined via flow cytometry. Monocyte CD16 expression rose with parasite-specific total IgG and IgG1 in healthy participants, but not in schistosome infected patients. Similar to parasite-specific IgG and IgG1, CD16 expression in healthy individuals is associated with protection against schistosome infection. This relationship indicates a mechanistic link between the innate and adaptive immune responses to helminth infection in protection against infection. Further understanding the elements of a protective immune response in schistosomiasis may aid in efforts to develop a protective vaccine against this disease.     

A Comparative Study of Peripheral Immune Responses to Taenia solium in Individuals with Parenchymal and Subarachnoid Neurocysticercosis

Background

The ability of Taenia solium to modulate the immune system likely contributes to their longevity in the human host. We tested the hypothesis that the nature of the immune response is related to the location of parasite and clinical manifestations of infection.

Methodology

Peripheral blood mononuclear cells (PBMC) were obtained from untreated patients with neurocysticercosis (NCC), categorized as having parenchymal or subarachnoid infection by the presence of cysts exclusively within the parenchyma or in subarachnoid spaces of the brain, and from uninfected (control) individuals matched by age and gender to each patient. Using multiplex detection technology, sera from NCC patients and controls and cytokine production by PBMC after T. solium antigen (TsAg) stimulation were assayed for levels of inflammatory and regulatory cytokines. PBMC were phenotyped by flow cytometry ex vivo and following in vitro stimulation with TsAg.

Principal Findings

Sera from patients with parenchymal NCC demonstrated significantly higher Th1 (IFN-γ/IL-12) and Th2 (IL-4/IL-13) cytokine responses and trends towards higher levels of IL-1β/IL-8/IL-5 than those obtained from patients with subarachnoid NCC. Also higher in vitro antigen-driven TNF-β secretion was detected in PBMC supernatants from parenchymal than in subarachnoid NCC. In contrast, there was a significantly higher IL-10 response to TsAg stimulation in patients with subarachnoid NCC compared to parenchymal NCC. Although no differences in regulatory T cells (Tregs) frequencies were found ex vivo, there was a trend towards greater expansion of Tregs upon TsAg stimulation in subarachnoid than in parenchymal NCC when data were normalized for the corresponding controls.

Conclusions/Significance

T. solium infection of the subarachnoid space is associated with an enhanced regulatory immune response compared to infection in the parenchyma. The resulting anti-inflammatory milieu may represent a parasite strategy to maintain a permissive environment in the host or diminish inflammatory damage from the host immune response in the central nervous system.     

Affective and Neural Reactivity to Criticism in Individuals High and Low on Perceived Criticism

People who have remitted from depression are at increased risk for relapse if they rate their relatives as being critical of them on a simple self-report measure of Perceived Criticism (PC). To explore neural mechanisms associated with this we used functional magnetic resonance imaging (fMRI) to examine how people with different levels of PC responded to hearing criticism from their own mothers. To maximize variability in affective reactivity, depressed, recovered depressed, and healthy control participants (n = 33) were classified as high or low in PC based on a median split. They were then exposed to personally-relevant critical and praising comments from their mothers. Perceived Criticism levels were unrelated to depression status and to negative mood change after hearing criticism. However, compared to low PC participants, those who scored high on PC showed differential activation in a network of regions associated with emotion reactivity and regulation, including increased amygdala activity and decreased reactions in prefrontal regulatory regions when they heard criticism. This was not the case for praise. Criticism may be a risk factor for relapse because it helps to “train” pathways characteristic of depressive information processing. The Perceived Criticism measure may help identify people who are more susceptible to this vulnerability.