The Underlying Neurobiological Mechanisms of Psychosis: Focus on Neurotransmission Dysregulation, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction.

Psychosis, defined as a set of symptoms that results in a distorted sense of reality, is observed in several psychiatric disorders in addition to schizophrenia. This paper reviews the literature relevant to the underlying neurobiology of psychosis. The dopamine hypothesis has been a major influence in the study of the neurochemistry of psychosis and in development of antipsychotic drugs. However, it became clear early on that other factors must be involved in the dysfunction involved in psychosis. In the current review, it is reported how several of these factors, namely dysregulation of neurotransmitters [dopamine, serotonin, glutamate, and γ-aminobutyric acid (GABA)], neuroinflammation, glia (microglia, astrocytes, and oligodendrocytes), the hypothalamic-pituitary-adrenal axis, the gut microbiome, oxidative stress, and mitochondrial dysfunction contribute to psychosis and interact with one another. Research on psychosis has increased knowledge of the complexity of psychotic disorders. Potential new pharmacotherapies, including combinations of drugs (with pre- and probiotics in some cases) affecting several of the factors mentioned above, have been suggested. Similarly, several putative biomarkers, particularly those related to the immune system, have been proposed. Future research on both pharmacotherapy and biomarkers will require better-designed studies conducted on an all stages of psychotic disorders and must consider confounders such as sex differences and comorbidity.

Alterations in brain network connectivity and subjective experience induced by psychedelics: a scoping review.

Intense interest surrounds current research on psychedelics, particularly regarding their potential in treating mental health disorders. Various studies suggest a link between the subjective effects produced by psychedelics and their therapeutic efficacy. Neuroimaging evidence indicates an association of changes in brain functional connectivity with the subjective effects of psychedelics. We conducted a review focusing on psychedelics and brain functional connectivity. The review focused on four psychedelic drugs: ayahuasca, psilocybin and LSD, and the entactogen MDMA. We conducted searches in databases of MEDLINE, Embase, APA PsycInfo and Scopus from inception to Jun 2023 by keywords related to functional connectivity and psychedelics. Using the PRISMA framework, we selected 24 articles from an initial pool of 492 for analysis. This scoping review and analysis investigated the effects of psychedelics on subjective experiences and brain functional connectivity in healthy individuals. The studies quantified subjective effects through psychometric scales, revealing significant experiences of altered consciousness, mood elevation, and mystical experiences induced by psychedelics. Neuroimaging results indicated alterations in the functional connectivity of psychedelics, with consistent findings across substances of decreased connectivity within the default mode network and increased sensory and thalamocortical connectivity. Correlations between these neurophysiological changes and subjective experiences were noted, suggesting a brain network basis of the psychedelics' neuropsychological impact. While the result of the review provides a potential neural mechanism of the subjective effects of psychedelics, direct clinical evidence is needed to advance their clinical outcomes. Our research serves as a foundation for further exploration of the therapeutic potential of psychedelics.

A fishermen-developed intervention reduced musculoskeletal load associated with commercial Dungeness crab harvesting.

This study characterized physical risk factors associated with injuries during a Dungeness crab harvesting task and evaluated the efficacy of a fishermen-developed ergonomic control (banger bar) in mitigating physical risk factors, including biomechanical loads in the low back, shoulders, and upper extremities, and postural instability. In a repeated-measures laboratory study, 25 healthy male participants performed manual crab harvesting tasks in five conditions: without any banger bar (control) and with 4 bars of differing heights or designs. The results showed that the ergonomic control reduced trunk and shoulder angles, L5/S1, and shoulder moments; muscle activities in low back, shoulders, and upper extremities; perceived exertion ratings; and postural sway measures. Moreover, these measures were lowest when the bar height was at 60 cm, indicating that the banger bar can reduce the risk of musculoskeletal injuries and postural instability, and that bar height is an important factor affecting these injury risk measures.

Testing for EGFR Variants in Pleural and Pericardial Effusion Cell-Free DNA in Patients With Non-Small Cell Lung Cancer.

Importance: Molecular testing in non-small cell lung cancer (NSCLC) is commonly limited by inadequate tumor sample. Plasma cell-free DNA (cfDNA) genotyping as a complementary test is specific but only moderately sensitive. Genotyping of cfDNA in pleural and pericardial effusion (PE-cfDNA) can further optimize molecular diagnostic yield and reduce the need for repeated biopsies. Objective: To prospectively validate droplet digital polymerase chain reaction (ddPCR) for detection of sensitizing EGFR variants and acquired Thr790Met variant (T790M) from PE-cfDNA in patients with NSCLC. Design, Setting, and Participants: This prospective diagnostic validation study was conducted between September 6, 2016, and January 21, 2021 at 2 major Hong Kong cancer centers. Patients with advanced NSCLC with both wild-type and variant EGFR status and exudative PE who underwent thoracocentesis or pericardiocentesis were randomly enrolled. Patients were either EGFR-tyrosine kinase inhibitor (TKI) naive (cohort 1) or EGFR-TKI treated but osimertinib naive (cohort 2). Enrolled patients underwent pleural- or pericardial-fluid and blood sampling for ddPCR EGFR testing. EGFR status results with ddPCR testing of PE-cfDNA and blood were compared with EGFR status in matched tumor biopsy or PE cell block samples. Main Outcomes and Measures: Specificity, sensitivity, and concordance of PE-cfDNA for detection of sensitizing EGFR variants and acquired T790M variation. Results: Among 171 patients (54% female) enrolled, there were 104 in cohort 1 and 67 in cohort 2. In cohort 1, 37% (38/102) were EGFR-variant positive; PE-cfDNA showed 97% sensitivity (95% CI, 92%-100%), 97% specificity (95% CI, 93%-100%), and 97% concordance (ĸ = 0.94, P < .001) for the detection of sensitizing EGFR variants. It was more sensitive than plasma in detecting sensitizing EGFR variants (97% vs 74%, P < .001). In cohort 2, 38% (15 of 40) were positive for the EGFR T790M variant; PE-cfDNA showed 87% sensitivity (95% CI, 69%-100%), 60% specificity (95% CI, 41%-79%), and 70% concordance (ĸ = 0.42, P = .004) for acquired T790M. The EGFR T790M variant was detected in 51% of PE-cfDNA vs 25% of PE cell block samples. Conclusions and Relevance: In this diagnostic study, EGFR variants could be accurately detected from PE-cfDNA in patients with NSCLC. More EGFR T790M was detected in PE-cfDNA than in guideline-recommended PE cell block preparations. These results suggest that PE-cfDNA can complement plasma and tumor genotyping for detecting EGFR variants in patients with advanced NSCLC.

Altered cortical processing of sensory input in Huntington disease mouse models.

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveals more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

Characterizing observable COVID-19 controls in Pacific Northwest grocery stores.

Utilizing a longitudinal, observational study, grocery store health and safety controls implemented during the COVID-19 pandemic across stores in two cities were characterized. Sixteen stores between Seattle, WA (n = 9) and Portland, OR (n = 7) were visited monthly by the study team from May 2020 to January 2021, and observations of controls were recorded using a standardized checklist in REDCap. The checklist included questions on the presence or absence of controls such as physical barriers, social distancing markers, required masking of customers, cleaning of check-out stands, and closures of store areas. Descriptive analyses were conducted to determine the proportion of stores with a certain control each month. Mixed-effects logistic regression was used to explore how controls changed over time, and whether differences were observed between cities or by income of the area the store serves. Source control (e.g., mask requirements) and engineering controls (e.g., physical barriers at checkout) were the most common and consistent controls observed across stores and over the study period. Controls such as having special hours for vulnerable populations, demarcations on aisles for directionality, and cleaning check-out stands between customers varied significantly over time (p < 0.05 in the mixed-effects model). Having an employee present to clean baskets and carts, as well as physical barriers between self-checkouts, were significantly more common in stores in areas above the median income (p < 0.05 in the mixed-effects model). To best protect workers and shoppers from infectious agents, controls should be evidence-based, consistently implemented across grocery stores, and coupled with administrative practices and policies to promote worker wellbeing.

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

Recent Advances in the Development of Biomarkers and Chemoradiotherapeutic Approaches for Nasopharyngeal Carcinoma.

Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) is endemic in Southern China, and the prognosis of this cancer has improved in part due to advances in radiotherapy (RT) techniques, broadened therapeutic options, and more precise prognostic stratification of patients. RT is the primary curative treatment of NPC, and the incorporation of chemotherapy (induction, concurrent, adjuvant) to RT has contributed to improved survival in patients with locoregionally advanced NPC. Concurrent chemoradiotherapy (CCRT) in combination with adjuvant or induction chemotherapy is now the standard treatment of locoregionally advanced NPC, but the ideal CCRT therapeutic strategy for NPC remains controversial. Plasma EBV DNA is the archetypal tumor-derived DNA in NPC, and three generations of studies have gradually expanded its clinical applications. Recently, the advent of whole exome/genome sequencing of NPC and the promising clinical activity of immune checkpoint inhibitors have also spurred interest in the development of newer biomarkers. This review will focus on two clinical advances in NPC research that have made substantial impact on the contemporary management of NPC: (1) The integration of plasma EBV DNA in an expanding spectrum of clinical indications, and the development of promising immune-related biomarkers; (2) the current development of CCRT with special emphasis on the use of induction and adjuvant chemotherapy, as well as the potential applications of metronomic chemotherapy and immune checkpoint inhibitors in the treatment of locoregionally advanced NPC.

Stress impacts sensory variability through cortical sensory activity motifs.

Medically unexplained symptoms in depression are common. These individual-specific complaints are often considered an 'idiom of distress', yet animal studies suggest that cortical sensory representations are flexible and influenced by spontaneous cortical activity. We hypothesized that stress would reveal activity dynamics in somatosensory cortex resulting in greater sensory-evoked response variability. Using millisecond resolution in vivo voltage sensitive dye (VSD) imaging in mouse neocortex, we characterized spontaneous regional depolarizations within limb and barrel regions of somatosensory cortex, or spontaneous sensory motifs, and their influence on sensory variability. Stress revealed an idiosyncratic increase in spontaneous sensory motifs that is normalized by selective serotonin reuptake inhibitor treatment. Spontaneous motif frequency is associated with increased variability in sensory-evoked responses, and we optogenetically demonstrate that regional depolarization in somatosensory cortex increases sensory-evoked variability for seconds. This reveals a putative circuit level target for changes in sensory processing and for unexplained physical complaints in stress-related psychopathology.

Strongly Coordinating Ligands To Form Weakly Coordinating Yet Functional Organometallic Anions.

Weakly coordinating anions (WCAs) are generally tailored to act as spectators with little or no function. Here we describe the implementation of strongly coordinating dianionic carboranyl N-heterocyclic carbenes (NHCs) to create organometallic -ate complexes of Au(I) that serve both as WCAs and functional catalysts. These organometallic WCAs can be utilized to form both heterobimetallic (Au(I)-/Ag(I)+; Au(I)-/Ir(I)+) and organometallic/main group ion pairs (Au(I)-/(CPh3+ or SiEt3+). Because parent unfunctionalized dianionic carboranyl NHC complex 3 is unstable in most solvents when paired with CPh3+, novel synthesis methodology was devised to create polyhalogenated carboranyl NHCs, which show superior stability toward electrophilic substitution and cyclometalation chemistry. Additionally, the WCAs containing polyhalogenated carboranyl NHCs are among the most active catalysts reported for the hydroamination of alkynes. This investigation has also produced the first examples of a low-coordinate Au(III) center with two cis accessible coordination sites and the first true dianionic carbene. These studies pave the way for the design of functional ion pairs that have the potential to participate in tandem or cooperative small-molecule activation and catalysis.

LFP clustering in cortex reveals a taxonomy of Up states and near-millisecond, ordered phase-locking in cortical neurons.

During slow-wave sleep and anesthesia, mammalian cortex exhibits a synchronized state during which neurons shift from a largely nonfiring to a firing state, known as an Up-state transition. Up-state transitions may constitute the default activity pattern of the entire cortex (Neske GT. Front Neural Circuits 9: 88, 2016) and could be critical to understanding cortical function, yet the genesis of such transitions and their interaction with single neurons is not well understood. It was recently shown that neurons firing at rates >2 Hz fire spikes in a stereotyped order during Up-state transitions (Luczak A, McNaughton BL, Harris KD. Nat Rev Neurosci 16: 745-755, 2015), yet it is still unknown if Up states are homogeneous and whether spiking order is present in neurons with rates <2 Hz (the majority). Using extracellular recordings from anesthetized cats and mice and from naturally sleeping rats, we show for the first time that Up-state transitions can be classified into several types based on the shape of the local field potential (LFP) during each transition. Individual LFP events could be localized in time to within 1-4 ms, more than an order of magnitude less than in previous studies. The majority of recorded neurons synchronized their firing to within ±5-15 ms relative to each Up-state transition. Simultaneous electrophysiology and wide-field imaging in mouse confirmed that LFP event clusters are cortex-wide phenomena. Our findings show that Up states are of different types and point to the potential importance of temporal order and millisecond-scale signaling by cortical neurons.NEW & NOTEWORTHY During cortical Up-state transitions in sleep and anesthesia, neurons undergo brief periods of increased firing in an order similar to that occurring in awake states. We show that these transitions can be classified into distinct types based on the shape of the local field potential. Transition times can be defined to <5 ms. Most neurons synchronize their firing to within ±5-15 ms of the transitions and fire in a consistent order.

Status of inflammation in relation to health related quality of life in hepatocellular carcinoma patients.

PURPOSE: Both Inflammation and health-related quality of life (HRQoL) are independent prognosticators in HCC patients. We hypothesized that inflammation can cause impairment in HRQoL and investigated the correlation between inflammatory status and HRQoL in HCC patients. METHODS: Clinical, laboratory and HRQoL (using EORTC QLQ-C30, QLQ-HCC18, C30 and HCC18 index-scores) data were prospectively collected from HCC patients at diagnosis. Correlation analyses were performed between HRQoL and inflammation-based markers including C-reactive protein (CRP), CRP/albumin ratio (CRP/alb), Glasgow Prognostic Score (GPS), Inflammation-Based Index (IBI) and Prognostic Index (PI). RESULTS: Among 445 HCC patients, higher inflammatory states were significantly correlated with worse HRQoL. For CRP and CRP/alb ratio, the HRQoL factors with higher correlations included C30 and HCC18 index-scores, certain QLQ-C30 domains and items ('physical functioning', 'role functioning', 'fatigue', 'pain', 'appetite loss') and QLQ-HCC18 items ('fatigue', 'body image', 'nutrition' and 'abdominal swelling'), where the Pearson's correlation coefficients were up to 0.416. Multivariate analyses indicated that worse HRQoL factors were significantly correlated with worse scores in GPS, IBI and PI. CONCLUSION: In HCC patients, inflammatory status correlates with HRQoL at presentation. In particular, relatively stronger correlations with CRP-based markers have been observed in HRQoL scales that assess constitutional symptoms (QLQ-C30 'physical functioning', 'role functioning', 'fatigue', 'appetite loss' and QLQ-HCC18 'fatigue' and 'nutrition') and tumor burden (QLQ-C30 'pain' and QLQ-HCC18 'abdominal swelling' and 'body image'). Future studies are warranted to evaluate whether intervention that reduces inflammation could improve HRQoL in HCC patients.

Correlations of health-related quality of life with serum inflammatory indicators IL-8 and mIBI in patients with hepatocellular carcinoma.

PURPOSE: Health-related quality of life (HRQoL) is a significant prognostic factor for overall survival in hepatocellular carcinoma (HCC) patients, and this is independent of stage and liver function. Inflammation plays a significant role in HCC development and progression. It was hypothesized that the inflammatory status of HCC patients may affect their HRQoL. The relationship between HRQoL and inflammatory status was explored using indicators IL-8 level and modified inflammation-based index (mIBI, based on IL-8, C-reactive protein, and albumin). METHODS: From 2007-2011, HCC patients were enrolled prospectively. Baseline HRQoL assessment utilized the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-HCC18; clinical and laboratory data were collected at diagnosis. Two summary indices, C30 and HCC18 index-scores, were calculated. Correlation analyses were performed between HRQoL and inflammatory markers. RESULTS: In the 445 patients studied, significant correlations were found between IL-8 levels and EORTC QLQ-C30, QLQ-HCC18, C30, and HCC18 index-scores. The strongest correlated factors were those reflective of constitutional symptoms, namely QLQ-C30 "appetite loss" (with Pearson's correlation coefficient, r=0.322, P<0.0001); QLQ-C30 "fatigue" (r=0.311, P<0.0001); QLQ-C30 "role functioning" (r=-0.305, P<0.0001); QLQ-HCC18 "nutrition" (r=0.317, P<0.0001); and QLQ-HCC18 "fatigue" (r=0.306, P<0.0001). In addition, moderate but significant correlations were also observed with HCC18 index score (r=0.321, P<0.0001), and C30 index score (r=0.306, P<0.0001). HRQoL factors were also significantly correlated with mIBI. CONCLUSION: Baseline HRQoL using the conventional assessments of EORTC QLQ-C30 and QLQ-HCC18, as well as C30 and HCC18 index-scores, significantly correlated with inflammatory indicators (IL-8 level and mIBI) in HCC patients. Among the strongest correlations were those between IL-8 level and the two index-scores, as well as HRQoL aspects that represent constitutional symptoms. When paralleled with molecular findings, traditional HRQoL assessment in HCC has gained a new level of understanding: pattern recognition within an HRQoL instrument could potentially identify patients with more severe inflammatory state.

Low-dose radiation: interagency collaboration on planning research could improve information on health effects.

In September 2017, the US Government Accountability Office (GAO) issued a report on the scientific basis for federal protections against the harmful effects of ionizing radiation-particularly low-dose radiation, or below about 100 millisieverts (10 rem). The report provided examples of how federal agencies developed and applied radiation protection requirements and guidance for workers and the public and examined the extent to which federal agencies funded epidemiological and radiobiological research on the health effects of low-dose radiation and their efforts at coordination of this research. The report found that agencies collaborated on individual projects on radiation's health effects but did not have a mechanism to coordinate research priorities. Consequently, GAO recommended that the Department of Energy (DOE) lead the development of a mechanism for interagency collaboration related to research on the health effects of low-dose radiation.

Podocalyxin is required for maintaining blood-brain barrier function during acute inflammation.

Podocalyxin (Podxl) is broadly expressed on the luminal face of most blood vessels in adult vertebrates, yet its function on these cells is poorly defined. In the present study, we identified specific functions for Podxl in maintaining endothelial barrier function. Using electrical cell substrate impedance sensing and live imaging, we found that, in the absence of Podxl, human umbilical vein endothelial cells fail to form an efficient barrier when plated on several extracellular matrix substrates. In addition, these monolayers lack adherens junctions and focal adhesions and display a disorganized cortical actin cytoskeleton. Thus, Podxl has a key role in promoting the appropriate endothelial morphogenesis required to form functional barriers. This conclusion is further supported by analyses of mutant mice in which we conditionally deleted a floxed allele of Podxl in vascular endothelial cells (vECs) using Tie2Cre mice (PodxlΔTie2Cre). Although we did not detect substantially altered permeability in naïve mice, systemic priming with lipopolysaccharide (LPS) selectively disrupted the blood-brain barrier (BBB) in PodxlΔTie2Cre mice. To study the potential consequence of this BBB breach, we used a selective agonist (TFLLR-NH2) of the protease-activated receptor-1 (PAR-1), a thrombin receptor expressed by vECs, neuronal cells, and glial cells. In response to systemic administration of TFLLR-NH2, LPS-primed PodxlΔTie2Cre mice become completely immobilized for a 5-min period, coinciding with severely dampened neuroelectric activity. We conclude that Podxl expression by CNS tissue vECs is essential for BBB maintenance under inflammatory conditions.

Good Vibrations: Resting-State Functional Connectivity Reflects Entrainment of Vasomotion.

In this issue of Neuron,Mateo et al. (2017) suggest that hemodynamic measures of resting-state functional connectivity in cortex are reporting the consequences of entrainment of arteriole vasomotion by neuronal activity.

Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine.

See Huang and Liston (doi:10.1093/awx166) for a scientific commentary on this article.Human depression is associated with glutamatergic dysfunction and alterations in resting state network activity. However, the indirect nature of human in vivo glutamate and activity assessments obscures mechanistic details. Using the chronic social defeat mouse model of depression, we determine how mesoscale glutamatergic networks are altered after chronic stress, and in response to the rapid acting antidepressant, ketamine. Transgenic mice (Ai85) expressing iGluSnFR (a recombinant protein sensor) permitted real-time in vivo selective characterization of extracellular glutamate and longitudinal imaging of mesoscale cortical glutamatergic functional circuits. Mice underwent chronic social defeat or a control condition, while spontaneous cortical activity was longitudinally sampled. After chronic social defeat, we observed network-wide glutamate functional hyperconnectivity in defeated animals, which was confirmed with voltage sensitive dye imaging in an independent cohort. Subanaesthetic ketamine has unique effects in defeated animals. Acutely, subanaesthetic ketamine induces large global cortical glutamate transients in defeated animals, and an elevated subanaesthetic dose resulted in sustained global increase in cortical glutamate. Local cortical inhibition of glutamate transporters in naïve mice given ketamine produced a similar extracellular glutamate phenotype, with both glutamate transients and a dose-dependent accumulation of glutamate. Twenty-four hours after ketamine, normalization of depressive-like behaviour in defeated animals was accompanied by reduced glutamate functional connectivity strength. Altered glutamate functional connectivity in this animal model confirms the central role of glutamate dynamics as well as network-wide changes after chronic stress and in response to ketamine.

Mesoscale Mapping of Mouse Cortex Reveals Frequency-Dependent Cycling between Distinct Macroscale Functional Modules.

Connectivity mapping based on resting-state activity in mice has revealed functional motifs of correlated activity. However, the rules by which motifs organize into larger functional modules that lead to hemisphere wide spatial-temporal activity sequences is not clear. We explore cortical activity parcellation in head-fixed, quiet awake GCaMP6 mice from both sexes by using mesoscopic calcium imaging. Spectral decomposition of spontaneous cortical activity revealed the presence of two dominant frequency modes (<1 and ∼3 Hz), each of them associated with a unique spatial signature of cortical macro-parcellation not predicted by classical cytoarchitectonic definitions of cortical areas. Based on assessment of 0.1-1 Hz activity, we define two macro-organizing principles: the first being a rotating polymodal-association pinwheel structure around which activity flows sequentially from visual to barrel then to hindlimb somatosensory; the second principle is correlated activity symmetry planes that exist on many levels within a single domain such as intrahemispheric reflections of sensory and motor cortices. In contrast, higher frequency activity >1 Hz yielded two larger clusters of coactivated areas with an enlarged default mode network-like posterior region. We suggest that the apparent constrained structure for intra-areal cortical activity flow could be exploited in future efforts to normalize activity in diseases of the nervous system.SIGNIFICANCE STATEMENT Increasingly, functional connectivity mapping of spontaneous activity is being used to reveal the organization of the brain. However, because the brain operates across multiple space and time domains a more detailed understanding of this organization is necessary. We used in vivo wide-field calcium imaging of the indicator GCaMP6 in head-fixed, awake mice to characterize the organization of spontaneous cortical activity at different spatiotemporal scales. Correlation analysis defines the presence of two to three superclusters of activity that span traditionally defined functional territories and were frequency dependent. This work helps define the rules for how different cortical areas interact in time and space. We provide a framework necessary for future studies that explore functional reorganization of brain circuits in disease models.

Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons.

Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps.

Systematic evaluation of circulating inflammatory markers for hepatocellular carcinoma.

BACKGROUNDS & AIMS: A number of circulating inflammatory factors are implicated in the pathogenesis and prognostication of hepatocellular carcinoma (HCC). We aim to evaluate the prognostication of multiple serum inflammatory factors simultaneously and develop an objective inflammatory score for HCC. METHODS: A prospective cohort of 555 patients with HCC with paired serum samples was accrued from 2009 to 2012. The blood levels of conventional inflammatory markers, namely C-reactive protein (CRP), albumin, neutrophils, lymphocytes and platelet, were determined, and 41 other exploratory markers were measured by a multiplex assay. The prognostication and interaction of markers were determined by univariate and multivarite analyses. RESULTS: The cohort was randomly divided into training cohort (n=139) and validation cohort (n=416). There were no differences in baseline characteristics between the two cohorts. In the training cohort, independent prognostic factors for overall survival included CRP (hazard ratio [HR] 1.107; P=.003), albumin (HR 0.953; P=.032) and interleukin-8 (HR=5.816; P<.001). We have modified the existing inflammation-based index (IBI) by adding serum interleukin-8 level. The modified IBI could stratify patients into four groups with distinct overall survival (P<.001). The results were also validated in the validation cohort. When compared with IBI and other conventional inflammatory markers, the modified IBI had better prognostic performance with higher c-index and homogeneity likelihood ratio chi-square. CONCLUSIONS: Among the conventional and exploratory circulating inflammatory markers, higher CRP, lower albumin and higher interleukin-8 were independent prognosticators. By combining these factors, a simple and accurate inflammatory index could be constructed.