Brain-wide ongoing activity is responsible for significant cross-trial BOLD variability.

A notorious issue of task-based functional magnetic resonance imaging (fMRI) is its large cross-trial variability. To quantitatively characterize this variability, the blood oxygenation level-dependent (BOLD) signal can be modeled as a linear summation of a stimulation-relevant and an ongoing (i.e. stimulation-irrelevant) component. However, systematic investigation on the spatiotemporal features of the ongoing BOLD component and how these features affect the BOLD response is still lacking. Here we measured fMRI responses to light onsets and light offsets in awake rats. The neuronal response was simultaneously recorded with calcium-based fiber photometry. We established that between-region BOLD signals were highly correlated brain-wide at zero time lag, including regions that did not respond to visual stimulation, suggesting that the ongoing activity co-fluctuates across the brain. Removing this ongoing activity reduced cross-trial variability of the BOLD response by ~30% and increased its coherence with the Ca2+ signal. Additionally, the negative ongoing BOLD activity sometimes dominated over the stimulation-driven response and contributed to the post-stimulation BOLD undershoot. These results suggest that brain-wide ongoing activity is responsible for significant cross-trial BOLD variability, and this component can be reliably quantified and removed to improve the reliability of fMRI response. Importantly, this method can be generalized to virtually all fMRI experiments without changing stimulation paradigms.

From eye movements to scanpath networks: A method for studying individual differences in expository text reading.

Eye movements have been examined as an index of attention and comprehension during reading in the literature for over 30 years. Although eye-movement measurements are acknowledged as reliable indicators of readers' comprehension skill, few studies have analyzed eye-movement patterns using network science. In this study, we offer a new approach to analyze eye-movement data. Specifically, we recorded visual scanpaths when participants were reading expository science text, and used these to construct scanpath networks that reflect readers' processing of the text. Results showed that low ability and high ability readers' scanpath networks exhibited distinctive properties, which are reflected in different network metrics including density, centrality, small-worldness, transitivity, and global efficiency. Such patterns provide a new way to show how skilled readers, as compared with less skilled readers, process information more efficiently. Implications of our analyses are discussed in light of current theories of reading comprehension.

Brain Activity Fluctuations Propagate as Waves Traversing the Cortical Hierarchy.

The brain exhibits highly organized patterns of spontaneous activity as measured by resting-state functional magnetic resonance imaging (fMRI) fluctuations that are being widely used to assess the brain's functional connectivity. Some evidence suggests that spatiotemporally coherent waves are a core feature of spontaneous activity that shapes functional connectivity, although this has been difficult to establish using fMRI given the temporal constraints of the hemodynamic signal. Here, we investigated the structure of spontaneous waves in human fMRI and monkey electrocorticography. In both species, we found clear, repeatable, and directionally constrained activity waves coursed along a spatial axis approximately representing cortical hierarchical organization. These cortical propagations were closely associated with activity changes in distinct subcortical structures, particularly those related to arousal regulation, and modulated across different states of vigilance. The findings demonstrate a neural origin of spatiotemporal fMRI wave propagation at rest and link it to the principal gradient of resting-state fMRI connectivity.

An open database of resting-state fMRI in awake rats.

Rodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular. Due to this rapid progress, publicly shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still rare. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publicly available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion and non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks obtained from the database.

Propagations of spontaneous brain activity in awake rats.

Slow propagations of spontaneous brain activity have been reported in multiple species. However, systematical investigation of the organization of such brain activity is still lacking. In this study, we analyzed propagations of spontaneous brain activity using a reference library of characteristic resting-state functional connectivity (RSFC) patterns in awake rodents. We found that transitions through multiple distinct RSFC patterns were reproducible not only in transition sequences but also in transition time delays. In addition, the organization of these transitions and their spatiotemporal dynamic patterns were revealed using a graphical model. We further identified prominent brain regions involved in these transitions. These results provide a comprehensive framework of brainwide propagations of spontaneous activity in awake rats. This study also offers a new tool to study the spatiotemporal dynamics of activity in the resting brain.

Functional atlas of the awake rat brain: A neuroimaging study of rat brain specialization and integration.

Connectivity-based parcellation approaches present an innovative method to segregate the brain into functionally specialized regions. These approaches have significantly advanced our understanding of the human brain organization. However, parallel progress in animal research is sparse. Using resting-state fMRI data and a novel, data-driven parcellation method, we have obtained robust functional parcellations of the rat brain. These functional parcellations reveal the regional specialization of the rat brain, which exhibited high within-parcel homogeneity and high reproducibility across animals. Graph analysis of the whole-brain network constructed based on these functional parcels indicates that the rat brain has a topological organization similar to humans, characterized by both segregation and integration. Our study also provides compelling evidence that the cingulate cortex is a functional hub region conserved from rodents to humans. Together, this study has characterized the rat brain specialization and integration, and has significantly advanced our understanding of the rat brain organization. In addition, it is valuable for studies of comparative functional neuroanatomy in mammalian brains.

Micro-CT study of the human cochlear aqueduct.

OBJECTIVE: The anatomic structure of the cochlear aqueduct (CA) in human temporal bone specimens was observed using micro-computed tomography (CT). MATERIALS AND METHODS: Micro-CT scanning of 18-µm-thick slices was performed on 30 slides of human temporal bone specimens to observe the CA structure and its relationship with its surroundings. The length, internal and external apertures, and the narrowest width of the CA were measured. The differences in CAs were compared between high jugular bulb (HJB) specimens and normal specimens. RESULTS: A large number of CA images were acquired using Micro-CT scanning, which clearly displayed the basic anatomic structures, stereotactic localizations, and adjacent relationships of the CAs. The whole course of a CA was 12.31 ± 3.60 mm, the diameter of the internal aperture was 465 ± 242 µm, the diameter of the external aperture was 2.88 ± 1.06 mm, the narrowest diameter was 601 ± 335 µm, the diameter of the opening of inferior cochlear vein (ICV) was 151 ± 50 µm, the distance between the internal aperture and ICV was 270 ± 197 µm, and the distance between the inferior margin of the internal acoustic meatus (IAM) and the top most part of the external aperture of the CA was 6.783 ± 2.15 mm. No bony obstruction of the CA or CA enlargement was observed in the specimens. A total of 28 CAs had one accompanying bony canal in the surroundings. The length and travelling of the CA were not affected by the level of the jugular bulb (JB). The variation of the travelling of the ICV was larger than that of the CA. CONCLUSION: Micro-CT adequately displayed the bony CA canal and provided a new method for anatomical studies of the CA and a basis for functional studies.

The effects of the auditory brainstem response before and after fluoro-gold injection in medial geniculate body.

OBJECTIVE: This study aimed to use the tree shrew as an otological model, not only to verify the location of the auditory pathway in tree shrews by fluoro-gold (FG) but also to elucidate the effects of the auditory brainstem response (ABR) before and after FG injection. METHODS: FG was injected into the medial geniculate body (MGB) of experimental group (n=10).The normal group (n=10) was inserted the microsyringe, which was not perfused FG. Hearing was assessed by testing ABRs before and after the operation. RESULTS: FG-labelled neurons were primarily distributed in the ipsilateral MGB, the ipsilateral and contralateral nuclei of the inferior colliculus (NIC), the superior olivary nucleus (SON), the dorsal cochlear nucleus (DCN), and the ventral cochlear nucleus (VCN). The ABR after FG injection caused a significant decrease in the wave amplitudes at 24 h that recovered by 72 h. However, the wave I-VI interpeak latencies in the right ear were shortened at 0 and 24 h post-surgery, whereas after 48 h, the interpeak latencies were prolonged. CONCLUSIONS: The FG retrograde tracing technique accurately displays the anatomical location of the auditory pathway in the tree shrew. The change in ABR waves suggested that there was a functional abnormality in the central auditory pathway after FG injection. The auditory thalamus may have self-regulating properties.

14-Thienyl methylene matrine (YYJ18), the derivative from matrine, induces apoptosis of human nasopharyngeal carcinoma cells by targeting MAPK and PI3K/Akt pathways in vitro.

BACKGROUND/AIMS: Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer with the highest incidence in South China. Previous studies have proved that matrine, a main alkaloid isolated from Sophora flavescens Ait, has antitumor activity against NPC. However, the effect is not so pronounced and the underlying mechanism remains largely unclear. Here we investigated whether 14-thienyl methylene matrine (YYJ18) that was derived from matrine could exert more effective suppression activity on NPC, along with the underlying mechanism. METHODS: NPC cell lines CNE1, CNE2 and HONE1 were treated with YYJ18. Cell proliferation and apoptosis were determined by MTT assay and flow cytometry. Activation of mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways were determined by Western blotting and quantitative RT-PCR. RESULTS: YYJ18 remarkably inhibited proliferation and induced apoptosis of all three NPC cell lines in a dose-dependent manner, especially in CNE2 cells. Furthermore, YYJ18 treatment significantly suppressed phosphorylation of p38 in CNE2 cells, but upregulated phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and Akt. Next, alterations in downstream signaling were found, including activation of BCL2-associated X protein (Bax), caspase-3 and inactivation of B-cell CLL/lymphoma 2 (Bcl-2). CONCLUSION: We demonstrate the potent inhibitory effects of 14-thienyl methylene matrine on NPC cells for the first time, which could be mediated by modulation of MAPK and PI3K/Akt pathways.

The effectiveness of self: A meta-analysis of using self-referential encoding techniques in education.

BACKGROUND: Self-related information is difficult to ignore and forget, which brings valuable implications for educational practice. Self-referential encoding techniques involve integrating self-referencing cues during the processing of learning material. However, the evidence base and effective implementation boundaries for these techniques in teaching and learning remain uncertain due to research variability. AIMS: The present meta-analysis aims to quantitatively synthesize the results from studies applying self-referential encoding techniques in education. METHODS: The analysis was based on data from 20 independent samples, including 1082 students from 13 primary studies identified through a systematic literature search. RESULTS: Results from random effect models show that incorporating self-referential encoding techniques improved learning (g = .40, 95% CI [.18, .62]). Subgroup analysis showed that the valence of learning material serves as a significant boundary condition for this strategy. The students' cohorts, types of learning materials, and research context did not moderate the effect sizes. CONCLUSIONS: Our results suggest that incorporating self-referential encoding techniques on negative materials shows an aversive effect. Overall, there is a universal benefit to using self-referential encoding techniques as an appropriate design guideline in educational contexts. Implications for teaching practice and future directions are discussed. Further studies are needed to investigate the effectiveness in more diverse educational and teaching situations.

Structural characteristics, immune-activating mechanisms in vitro, and immunomodulatory effects in vivo of the exopolysaccharide EPS53 from Streptococcus thermophilus XJ53.

Our previous investigations have successfully identified the repeating structural units of EPS53, an exopolysaccharide derived from Streptococcus thermophilus XJ53 fermented milk, and substantiated its potential immunomodulatory properties. The present study further elucidated the structural characteristics of EPS53 and investigated the underlying mechanisms governing its in vitro immunoreactivity as well as its in vivo immunoreactivity. The results obtained from multi-detector high performance gel filtration chromatography revealed that EPS53 adopted a rigid rod conformation in aqueous solution, with the weight-average molecular weight of 1464 kDa, the number-average molecular weight of 694 kDa, and the polydispersity index of 2.11. Congo red experiment confirmed the absence of a triple helix conformation. Scanning electron microscopy showed that EPS53 displayed a three-dimensional fibrous structure covered with flakes. The in vitro findings indicated that EPS53 enhanced phagocytosis ability, reactive oxygen species (ROS) production, and cytokine levels of macrophages via the TLR4-mediated NF-κB/MAPK signaling pathways as confirmed by immunofluorescence staining experiments, inhibition blocking experiments, and Western blot assay. Additionally, the in vivo experiments demonstrated that EPS53 significantly increased macrophage and neutrophil number while enhancing NO and ROS levels in zebrafish larvae; thus, providing further evidence for the immunomodulatory efficacy of EPS53.

Large-Scale Preparation of Carboxylated Cellulose Nanocrystals and Their Application for Stabilizing Pickering Emulsions.

Cellulose nanocrystals (CNCs) with varied unique properties have been widely used in emulsions, nanocomposites, and membranes. However, conventional CNCs for industrial use were usually prepared through acid hydrolysis or heat-controlled methods with sulfuric acid. This most commonly used acid method generally suffers from low yields, poor thermal stability, and potential environmental pollution. Herein, we developed a high-efficiency and large-scale preparation strategy to produce carboxylated cellulose nanocrystals (Car-CNCs) via carboxymethylation-enhanced ammonium persulfate (APS) oxidation. After carboxymethylation, the wood fibers could form unique "balloon-like" structures with abundant exposed hydroxy groups, which facilitated exfoliating fibril bundles into individual nanocrystals during the APS oxidation process. The production process under controlled temperature, time period, and APS concentrations was optimized and the resultant Car-CNCs exhibited a typical structure with narrow diameter distributions. In particular, the final Car-CNCs exhibited excellent thermal stability (≈346.6 °C) and reached a maximum yield of 60.6%, superior to that of sulfated cellulose nanocrystals (Sul-CNCs) prepared by conventional acid hydrolysis. More importantly, compared to the common APS oxidation, our two-step collaborative process shortened the oxidation time from more than 16 h to only 30 min. Therefore, our high-efficiency method may pave the way for the up-scaled production of carboxylated nanocrystals. More importantly, Car-CNCs show potential for stabilizing Pickering emulsions that can withstand changeable environments, including heating, storage, and centrifugation, which is better than the conventional Sul-CNC-based emulsions.

A consensus protocol for functional connectivity analysis in the rat brain.

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.

Alterations of Regional Homogeneity in Children With Congenital Sensorineural Hearing Loss: A Resting-State fMRI Study.

Background: Brain functional alterations have been observed in children with congenital sensorineural hearing loss (CSNHL). The purpose of this study was to assess the alterations of regional homogeneity in children with CSNHL. Methods: Forty-five children with CSNHL and 20 healthy controls were enrolled into this study. Brain resting-state functional MRI (rs-fMRI) for regional homogeneity including the Kendall coefficient consistency (KCC-ReHo) and the coherence-based parameter (Cohe-ReHo) was analyzed and compared between the two groups, i.e., the CSNHL group and the healthy control group. Results: Compared to the healthy controls, children with CSNHL showed increased Cohe-ReHo values in left calcarine and decreased values in bilateral ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). Children with CSNHL also had increased KCC-ReHo values in the left calcarine, cuneus, precentral gyrus, and right superior parietal lobule (SPL) and decreased values in the left VLPFC and right DLPFC. Correlations were detected between the ReHo values and age of the children with CSNHL. There were positive correlations between ReHo values in the pre-cuneus/pre-frontal cortex and age (p < 0.05). There were negative correlations between ReHo values in bilateral temporal lobes, fusiform gyrus, parahippocampal gyrus and precentral gyrus, and age (p < 0.05). Conclusion: Children with CSNHL had RoHo alterations in the auditory, visual, motor, and other related brain cortices as compared to the healthy controls with normal hearing. There were significant correlations between ReHo values and age in brain regions involved in information integration and processing. Our study showed promising data using rs-fMRI ReHo parameters to assess brain functional alterations in children with CSNHL.

Automatic Brain Extraction for Rodent MRI Images.

Rodent models are increasingly important in translational neuroimaging research. In rodent neuroimaging, particularly magnetic resonance imaging (MRI) studies, brain extraction is a critical data preprocessing component. Current brain extraction methods for rodent MRI usually require manual adjustment of input parameters due to widely different image qualities and/or contrasts. Here we propose a novel method, termed SHape descriptor selected Extremal Regions after Morphologically filtering (SHERM), which only requires a brain template mask as the input and is capable of automatically and reliably extracting the brain tissue in both rat and mouse MRI images. The method identifies a set of brain mask candidates, extracted from MRI images morphologically opened and closed sequentially with multiple kernel sizes, that match the shape of the brain template. These brain mask candidates are then merged to generate the brain mask. This method, along with four other state-of-the-art rodent brain extraction methods, were benchmarked on four separate datasets including both rat and mouse MRI images. Without involving any parameter tuning, our method performed comparably to the other four methods on all datasets, and its performance was robust with stably high true positive rates and low false positive rates. Taken together, this study provides a reliable automatic brain extraction method that can contribute to the establishment of automatic pipelines for rodent neuroimaging data analysis.

GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia.

The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.

A Role for the Claustrum in Salience Processing?

The claustrum (CLA) is a subcortical structure, present only in mammals, whose function remains uncertain. Previously, using resting-state functional magnetic resonance imaging (rs-fMRI) in awake head-fixed rats, we found evidence that the CLA is part of the rodent homolog of the default mode network (DMN; Smith et al., 2017). This network emerged as strong functional connections between the medial prefrontal cortex (mPFC), mediodorsal (MD) thalamus, and CLA in the awake state, which was not present following administration of isoflurane anesthesia. In the present report, we review evidence indicating that the rodent CLA also has connections with structures identified in the rodent homolog of the salience network (SN), a circuit that directs attention towards the most relevant stimuli among a multitude of sensory inputs (Seeley et al., 2007; Menon and Uddin, 2010). In humans, this circuit consists of functional connections between the anterior cingulate cortex (ACC) and a region that encompasses both the CLA and insular cortex. We further go on to review the similarities and differences between the functional and anatomical connections of the CLA and insula in rodents using both rs-fMRI and neuroanatomical tracing, respectively. We analyze in detail the connectivity of the CLA with the cingulate cortex, which is a major node in the SN and has been shown to modulate attention. When considered with other recent behavior and physiology studies, the data reveal a role for the CLA in salience-guided orienting. More specifically, we hypothesize that limbic information from mPFC, MD thalamus, and the basolateral amygdala (BLA) are integrated by the CLA to guide modality-related regions of motor and sensory cortex in directing attention towards relevant (i.e., salient) sensory events.

Anatomical Variations of the Human Cochlea Determined from Micro-CT and High-Resolution CT Imaging and Reconstruction.

Understanding the anatomical variations in the human cochlea is important for cochlear implants. This study examined these variations using a reconstructed fusion model of the skull and temporal bone. The three-dimensional (3D) digital model of the temporal bone was reconstructed from multiple axial micro-computed tomography (CT) scans of temporal bone and high resolution CT of the skull from 15 cadavers. A skull model was reconstructed and merged with the reconstructed temporal bone. The 3D relationship between the cochlea and the skull's mid-sagittal plane was analyzed. The α and ß angles of the cochlear autogenous rotation and bottom position, respectively, further subdivided the cochlear spatial orientation. The relationship between the base of the cochlea and the round window was evaluated with the Φ angle. Cochlear size was measured and the relationship was statistically analyzed. Cochlear implant electrode arrays were observed in five cases of right-temporal bone specimens. The α, ß, and Φ angles were 46.01 ± 9.65, 56.79 ± 3.58, and 44.41 ± 7.23, respectively. The α angle varied greatly and was negatively correlated to the Φ angle (correlation coefficient = -0.211, P < 0.05). Among the five specimens, the α and Φ angle of the 2R and 4R cochlear specimens was lower and higher than the mean value, respectively. These measurements revealed variations in the size and position of the cochlea. Some of these variations may require surgical adjustments for insertion of electrodes with cochlear implants and present a greater challenge for implantation of cochlear electrode implantation. These data also provide a better understanding of variations in human cochlear anatomy. Anat Rec, 301:1086-1095, 2018. © 2017 Wiley Periodicals, Inc.

Image-guided chemotherapy with specifically tuned blood brain barrier permeability in glioma margins.

Blood-brain barrier (BBB) disruption is frequently observed in the glioma region. However, the tumor uptake of drugs is still too low to meet the threshold of therapeutic purpose. Method: A tumor vasculature-targeted nanoagonist was developed. Glioma targeting specificity of the nanoagonist was evaluated by in vivo optical imaging. BBB permeability at the glioma margin was quantitatively measured by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Single-photon emission computed tomography imaging/computed tomography (SPECT/CT) quantitatively determined the glioma uptake of the radiolabeled model drug. T2-weighted MRI monitored the tumor volume. Results: Immunostaining studies demonstrated that the BBB remained partially intact in the invasive margin of patients' gliomas regardless of their malignancies. DCE-MRI showed that vascular permeability in the glioma margin reached its maximum at 45 min post nanoagonist administration. In vivo optical imaging indicated the high glioma targeting specificity of the nanoagonist. SPECT/CT showed the significantly enhanced glioma uptake of the model drug after pre-treatment with the nanoagonist. Image-guided paclitaxel injection after nanoagonist-mediated BBB modulation more efficiently attenuated tumor growth and extended survival than in animal models treated with paclitaxel or temozolomide alone. Conclusion: Thus, image-guided drug delivery following BBB permeability modulation holds promise to enhance the efficacy of chemotherapeutics to glioma.