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Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.

Parkinson’s disease (PD) is a widespread degenerative syndrome that affects the nervous system. Its early appearing symptoms include tremor, rigidity, and vocal impairment (dysphonia). Consequently, speech indicators are important in the identification of PD based on dysphonic signs. In this regard, computer-aided-diagnosis systems based on machine learning can be useful in assisting clinicians in identifying PD patients. In this work, we evaluate the performance of machine learning based techniques for PD diagnosis based on dysphonia symptoms. Several machine learning techniques were considered and trained with a set of twenty-two voice disorder measurements to classify healthy and PD patients. These machine learning methods included linear discriminant analysis (LDA), knearest-neighbors (k-NN), naïve Bayes (NB), regression trees (RT), radial basis function neural networks (RBFNN), support vector machine (SVM), and Mahalanobis distance classifier. We evaluated the performance of these methods by means of a tenfold cross validation protocol. Experimental results show that the SVM classifier achieved higher average performance than all other classifiers in terms of overall accuracy, G-mean, and area under the curve of the receiver operating characteristic plot. The SVM classifier achieved higher performance measures than the majority of the other classifiers also in terms of sensitivity, specificity, and F-measure statistics. The LDA, k-NN and RT achieved the highest average precision. The RBFNN method yielded the highest F-measure.; however, it performed poorly in terms of other performance metrics. Finally, ttests were performed to evaluate statistical significance of the results, confirming that the SVM outperformed most of the other classifiers on the majority of performance measures. SVM is a promising method for identifying PD patients based on classification of dysphonia measurements.

As science and technology evolve, there is an increasing need for promotion of international scientific exchange. Collaborations, while offering substantial opportunities for scientists and benefit to society, also present challenges for those working with animal models, such as non-human primates (NHPs). Diversity in regulation of animal research is sometimes mistaken for the absence of common international welfare standards. Here, the ethical and regulatory protocols for 13 countries that have guidelines in place for biomedical research involving NHPs were assessed with a focus on neuroscience. Review of the variability and similarity in trans-national NHP welfare regulations extended to countries in Asia, Europe and North America. A tabulated resource was established to advance solution-oriented discussions and scientific collaborations across borders. Our aim is to better inform the public and other stakeholders. Through cooperative efforts to identify and analyze information with reference to evidence-based discussion, the proposed key ingredients may help to shape and support a more informed, open framework. This framework and resource can be expanded further for biomedical research in other countries.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain modulation and rehabilitation technique used in patients with neuropsychiatric diseases. rTMS can structurally remodel or functionally induce activities of specific cortical regions and has developed to an important therapeutic method in such patients. Magnetic resonance imaging (MRI) provides brain data that can be used as an explanation tool for the neural mechanisms underlying rTMS effects; brain alterations related to different functions or structures may be reflected in changes in the interaction and influence of brain connections within intrinsic specific networks. In this review, we discuss the technical details of rTMS and the biological interpretation of brain networks identified with MRI analyses, comprehensively summarize the neurobiological effects in rTMS-modulated individuals, and elaborate on changes in the brain network in patients with various neuropsychiatric diseases receiving rehabilitation treatment with rTMS. We conclude that brain connectivity network analysis based on MRI can reflect alterations in functional and structural connectivity networks comprising adjacent and separated brain regions related to stimulation sites, thus reflecting the occurrence of intrinsic functional integration and neuroplasticity. Therefore, MRI is a valuable tool for understanding the neural mechanisms of rTMS and practically tailoring treatment plans for patients with neuropsychiatric diseases.

ABSTRACTProtective antigen (PA)-based vaccines are effective in preventing the development of fatal anthrax disease both in humans and in relevant animal models. The Bacillus anthracistoxins lethal toxin (lethal factor [LF] plus PA) and edema toxin (edema factor [EF] plus PA) are essential for the establishment of the infection, as inactivation of these toxins results in attenuation of the pathogen. Since the toxins reach high toxemia levels at the bacteremic stages of the disease, the CDC's recommendations include combining antibiotic treatment with antitoxin (anti-PA) immunotherapy. We demonstrate here that while treatment with a highly potent neutralizing monoclonal antibody was highly efficient as postexposure prophylaxis treatment, it failed to protect rabbits with any detectable bacteremia (≥10 CFU/ml). In addition, we show that while PA vaccination was effective against a subcutaneous spore challenge, it failed to protect rabbits against systemic challenges (intravenous injection of vegetative bacteria) with the wild-type Vollum strain or a toxin-deficient mutant. To test the possibility that additional proteins, which are secreted by the bacteria under pathogenicity-stimulating conditions in vitro, may contribute to the vaccine's potency, we immunized rabbits with a secreted protein fraction from a toxin-null mutant. The antiserum raised against the secreted fraction reacts with the bacteria in an immunofluorescence assay. Immunization with the secreted protein fraction did not protect the rabbits against a systemic challenge with the fully pathogenic bacteria. Full protection was obtained only by a combined vaccination with PA and the secreted protein fraction. Therefore, these results indicate that an effective antiserum treatment in advanced stages of anthrax must include toxin-neutralizing antibodies in combination with antibodies against bacterial cell targets.

AbstractNumerous studies have demonstrated functional magnetic resonance imaging (fMRI)-based resting-state functional connectivity (RSFC) between cortical areas. Recent evidence suggests that synchronous fluctuations in blood oxygenation level-dependent fMRI reflect functional organization at a scale finer than that of visual areas. In this study, we investigated whether RSFCs within and between lower visual areas are retinotopically organized and whether retinotopically organized RSFC merely reflects cortical distance. Subjects underwent retinotopic mapping and separately resting-state fMRI. Visual areas V1, V2, and V3, were subdivided into regions of interest (ROIs) according to quadrants and visual field eccentricity. Functional connectivity (FC) was computed based on Pearson's linear correlation (correlation), and Pearson's linear partial correlation (correlation between two time courses after the time courses from all other regions in the network are regressed out). Within a quadrant, within visual areas, all correlation and nearly all partial correlation FC measures showed statistical significance. Consistently in V1, V2, and to a lesser extent in V3, correlation decreased with increasing eccentricity separation. Consistent with previously reported monkey anatomical connectivity, correlation/partial correlation values between regions from adjacent areas (V1-V2 and V2-V3) were higher than those between nonadjacent areas (V1-V3). Within a quadrant, partial correlation showed consistent significance between regions from two different areas with the same or adjacent eccentricities. Pairs of ROIs with similar eccentricity showed higher correlation/partial correlation than pairs distant in eccentricity. Between dorsal and ventral quadrants, partial correlation between common and adjacent eccentricity regions within a visual area showed statistical significance; this extended to more distant eccentricity regions in V1. Within and between quadrants, correlation decreased approximately linearly with increasing distances separating the tested ROIs. Partial correlation showed a more complex dependence on cortical distance: it decreased exponentially with increasing distance within a quadrant, but was best fit by a quadratic function between quadrants. We conclude that RSFCs within and between lower visual areas are retinotopically organized. Correlation-based FC is nonselectively high across lower visual areas, even between regions that do not share direct anatomical connections. The mechanisms likely involve network effects caused by the dense anatomical connectivity within this network and projections from higher visual areas. FC based on partial correlation, which minimizes network effects, follows expectations based on direct anatomical connections in the monkey visual cortex better than correlation. Last, partial correlation-based retinotopically organized RSFC reflects more than cortical distance effects.

AbstractThe influence of the global average signal (GAS) on functional-magnetic resonance imaging (fMRI)–based resting-state functional connectivity is a matter of ongoing debate. The global average fluctuations increase the correlation between functional systems beyond the correlation that reflects their specific functional connectivity. Hence, removal of the GAS is a common practice for facilitating the observation of network-specific functional connectivity. This strategy relies on the implicit assumption of a linear-additive model according to which global fluctuations, irrespective of their origin, and network-specific fluctuations are super-positioned. However, removal of the GAS introduces spurious negative correlations between functional systems, bringing into question the validity of previous findings of negative correlations between fluctuations in the default-mode and the task-positive networks. Here we present an alternative method for estimating global fluctuations, immune to the complications associated with the GAS. Principal components analysis was applied to resting-state fMRI time-series. A global-signal effect estimator was defined as the principal component (PC) that correlated best with the GAS. The mean correlation coefficient between our proposed PC-based global effect estimator and the GAS was 0.97±0.05, demonstrating that our estimator successfully approximated the GAS. In 66 out of 68 runs, the PC that showed the highest correlation with the GAS was the first PC. Since PCs are orthogonal, our method provides an estimator of the global fluctuations, which is uncorrelated to the remaining, network-specific fluctuations. Moreover, unlike the regression of the GAS, the regression of the PC-based global effect estimator does not introduce spurious anti-correlations beyond the decrease in seed-based correlation values allowed by the assumed additive model. After regressing this PC-based estimator out of the original time-series, we observed robust anti-correlations between resting-state fluctuations in the default-mode and the task-positive networks. We conclude that resting-state global fluctuations and network-specific fluctuations are uncorrelated, supporting a Resting-State Linear-Additive Model. In addition, we conclude that the network-specific resting-state fluctuations of the default-mode and task-positive networks show artifact-free anti-correlations.

A multi-component microarray, applying a novel analysis algorithm, was developed for quantitative evaluation of the SARS-CoV-2 vaccines’ immunogenicity. The array enables simultaneous quantitation of IgG, IgM, and IgA, specific to the SARS-CoV-2 spike, receptor binding domain, and nucleocapsid proteins. The developed methodology is based on calculating an apparent immunoglobulin signal from the linear range of the fluorescent read-outs generated by scanning the microarray slides at different exposure times. A dedicated algorithm, employing a rigorous set of embedded conditions, then generates a normalized signal for each of the unique assays. Qualification of the multi-component array performance (evaluating linearity, extended dynamic-range, specificity, precision, and accuracy) was carried out with an in-house COVID-19, qRT-PCR positive serum, as well as pre-pandemic commercial negative sera. Results were compared to the WHO international standard for anti-SARS-CoV-2 immunoglobulins. Specific IgG, IgM, and IgA signals obtained by this array enabled successful discrimination between SARS-CoV-2 q-RT-PCR positive (seroconverted SARS-CoV-2 patients) and negative (naïve) samples. This array is currently used for evaluation of the humoral response to BriLife, the VSV-based Israeli vaccine during phase I/II clinical trials.

Background: L1-cell adhesion molecule (L1-CAM) is a cell adhesion receptor of the immunoglobulin superfamily, known for its roles in nerve cell function. While originally believed to be present only in brain cells, in recent years L1-CAM has been detected in other tissues, and in a variety of cancer cells, including some common types of human cancer. Objective/methods: We review the prevalence of L1-CAM in human cancer, the possible mechanisms involved in L1-CAM-mediated tumorigenesis, and cancer therapies based upon L1-CAM antibody treatment. Results/conclusions: In colon cancer cells, the L1-CAMgene was identified as a target of the Wnt/β-catenin-TCF signaling pathway, and L1-CAM was exclusively detected at the invasive front of colon and ovarian cancer tissue. The expression of L1-CAM in normal and cancer cells enhanced tumorigenesis and conferred metastasis in colon cancer cells. Antibodies against the L1-CAM ectodomain severely inhibited the proliferation of a variety of cancer cells in culture and reduced tumor burden when injected into mice harboring cancer cells expressing L1-CAM. These results, in addition to the presence of L1-CAM on the cell surface and its restricted distribution in normal tissues, make it an ideal target for tumor therapy.

Perfusion‐based MRI measures cerebral blood flow (CBF) at the capillary level and can be used for functional studies based on the tight spatial coupling between brain activity and blood flow. Obtaining functional CBF maps with high spatial resolution is a major challenge because the CBF signal is intrinsically low and the SNR is critical. In the present work, CBF‐based functional imaging was performed at a considerably smaller voxel size than previously reported in humans. High‐resolution CBF maps were obtained with voxel sizes as small as 0.9 × 0.9 × 1.5 mm3in the human brain. High sensitivity was made possible by signal‐to‐noise gains at the high magnetic field of 7 T and by using a novel RF combination coil design. In addition, a reduction of the field‐of‐view was critical to achieve 0.9‐mm in‐plane resolution with gradient‐echo echo‐planar imaging in a single shot. Functional CBF data were compared with functional BOLD data to reveal that, for CBF, large contrast‐ to‐noise gains were obtained at high spatial resolution, indicating that the functional CBF response was more localized. High‐resolution functional CBF imaging is significant for neuroscience research because it provides better localization and more specific information than BOLD for monitoring brain function. Magn Reson Med 47:903–911, 2002. © 2002 Wiley‐Liss, Inc.

In agreement with optical imaging studies, previous fMRI studies have reported an initial decrease (i.e. the initial dip) in the BOLD response, which is believed to arise from an increase in oxygen consumption and to be mostly microvascular. To date, experimental studies of the initial dip in humans have been performed at fields up to 4 T, with relatively low spatial resolution. Because the sensitivity to microvascular contribution is increased at high magnetic fields, the present study investigated the initial dip at 7 T. In addition, to reduce the partial volume effect, the study is conducted at a high spatial resolution. The initial dip was detected in all subjects studied and was found to reside mostly in the gray matter. The relative amplitude of the early response was found to be 0.6, higher than that at 4 T (0.3) and 1.5 T (0.11). In addition, based on the assumption that the initial dip is a result of increased oxygen utilization, the fractional change in oxygen utilization was estimated to be 40% of that of the fractional change in cerebral blood flow. These results are in agreement with the notion that the initial dip arises from an increase in oxygen consumption. Copyright © 2001 John Wiley & Sons, Ltd. Abbreviations used: CBF cerebral blood flow CMRO2 cerebral metabolic rate of oxygen OVS outer volume suppression PVE partial volume effect

In agreement with optical imaging studies, previous fMRI studies have reported an initial decrease (i.e. the initial dip) in the BOLD response, which is believed to arise from an increase in oxygen consumption and to be mostly microvascular. To date, experimental studies of the initial dip in humans have been performed at fields up to 4 T, with relatively low spatial resolution. Because the sensitivity to microvascular contribution is increased at high magnetic fields, the present study investigated the initial dip at 7 T. In addition, to reduce the partial volume effect, the study is conducted at a high spatial resolution. The initial dip was detected in all subjects studied and was found to reside mostly in the gray matter. The relative amplitude of the early response was found to be 0.6, higher than that at 4 T (0.3) and 1.5 T (0.11). In addition, based on the assumption that the initial dip is a result of increased oxygen utilization, the fractional change in oxygen utilization was estimated to be 40% of that of the fractional change in cerebral blood flow. These results are in agreement with the notion that the initial dip arises from an increase in oxygen consumption. Copyright © 2001 John Wiley & Sons, Ltd.

This article describes experimental studies performed to demonstrate the feasibility of BOLD fMRI using echo‐planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high‐resolution multishot EPI sequences. Changes in R*2arising from visual stimulation were experimentally determined using fMRI measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fMRI can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45:588–594, 2001. © 2001 Wiley‐Liss, Inc.

An application of an active method in order to compute highly accurate 3D localization of point features from few projections is presented. The angle of projection of the image is controlled by the system and directed to extract 3D information from the environment in a manner leading to accurate location in less computation.

ABSTRACTTreatment of anthrax is challenging, especially during the advanced stages of the disease. Recently, the Centers for Disease Control and Prevention (CDC) updated its recommendations for postexposure prophylaxis and treatment of exposed populations (before and after symptom onset). These recommendations distinguished, for the first time, between systemic disease with and without meningitis, a common and serious complication of anthrax. The CDC considers all systemic cases meningeal unless positively proven otherwise. The treatment of patients suffering from systemic anthrax with suspected or confirmed meningitis includes the combination of three antibiotics, i.e., a fluoroquinolone (levofloxacin or ciprofloxacin), a β-lactam (meropenem or imipenem), and a protein synthesis inhibitor (linezolid or clindamycin). In addition, treatment with an antitoxin (anti-protective antigen antibodies) and dexamethasone should be applied. Since the efficacy of most of these treatments has not been demonstrated, especially in animal meningitis models, we developed an anthrax meningitis model in rabbits and tested several of these recommendations. We demonstrated that, in this model, ciprofloxacin, linezolid, and meropenem were ineffective as single treatments, while clindamycin was highly effective. Furthermore, combined treatments of ciprofloxacin and linezolid or ciprofloxacin and dexamethasone failed in treating rabbits with meningitis. We demonstrated that dexamethasone actually hindered blood-brain barrier penetration by antibiotics, reducing the effectiveness of antibiotic treatment of anthrax meningitis in this rabbit model.