Graph theory approaches to functional network organization in brain disorders: A critique for a brave new small-world

Over the past two decades, resting-state functional connectivity (RSFC) methods have provided new insights into the network organization of the human brain. Studies of brain disorders such as Alzheimer’s disease or depression have adapted tools from graph theory to characterize differences between healthy and patient populations. Here, we conducted a review of clinical network neuroscience, summarizing methodological details from 106 RSFC studies. Although this approach is prevalent and promising, our review identified four challenges. First, the composition of networks varied remarkably in terms of region parcellation and edge definition, which are fundamental to graph analyses. Second, many studies equated the number of connections across graphs, but this is conceptually problematic in clinical populations and may induce spurious group differences. Third, few graph metrics were reported in common, precluding meta-analyses. Fourth, some studies tested hypotheses at one level of the graph without a clear neurobiological rationale or considering how findings at one level (e.g., global topology) are contextualized by another (e.g., modular structure). Based on these themes, we conducted network simulations to demonstrate the impact of specific methodological decisions on case-control comparisons. Finally, we offer suggestions for promoting convergence across clinical studies in order to facilitate progress in this important field

Neural connectivity biotypes: associations with internalizing problems throughout adolescence.

BackgroundNeurophysiological patterns may distinguish which youth are at risk for the well-documented increase in internalizing symptoms during adolescence. Adolescents with internalizing problems exhibit altered resting-state functional connectivity (RSFC) of brain regions involved in socio-affective processing. Whether connectivity-based biotypes differentiate adolescents' levels of internalizing problems remains unknown.MethodSixty-eight adolescents (37 females) reported on their internalizing problems at ages 14, 16, and 18 years. A resting-state functional neuroimaging scan was collected at age 16. Time-series data of 15 internalizing-relevant brain regions were entered into the Subgroup-Group Iterative Multi-Model Estimation program to identify subgroups based on RSFC maps. Associations between internalizing problems and connectivity-based biotypes were tested with regression analyses.ResultsTwo connectivity-based biotypes were found: a Diffusely-connected biotype (N = 46), with long-range fronto-parietal paths, and a Hyper-connected biotype (N = 22), with paths between subcortical and medial frontal areas (e.g. affective and default-mode network regions). Higher levels of past (age 14) internalizing problems predicted a greater likelihood of belonging to the Hyper-connected biotype at age 16. The Hyper-connected biotype showed higher levels of concurrent problems (age 16) and future (age 18) internalizing problems.ConclusionsDifferential patterns of RSFC among socio-affective brain regions were predicted by earlier internalizing problems and predicted future internalizing problems in adolescence. Measuring connectivity-based biotypes in adolescence may offer insight into which youth face an elevated risk for internalizing disorders during this critical developmental period

Multi-generation OH oxidation as a source for highly oxygenated organic molecules from aromatics

Recent studies have recognised highly oxygenated organic molecules (HOMs) in the atmosphere as important in the formation of secondary organic aerosol (SOA). A large number of studies have focused on HOM formation from oxidation of biogenically emitted monoterpenes. However, HOM formation from anthropogenic vapours has so far received much less attention. Previous studies have identified the importance of aromatic volatile organic compounds (VOCs) for SOA formation. In this study, we investigated several aromatic compounds, benzene (C6H6), toluene (C7H8), and naphthalene (C10H8), for their potential to form HOMs upon reaction with hydroxyl radicals (OH). We performed flow tube experiments with all three VOCs and focused in detail on benzene HOM formation in the Julich Plant Atmosphere Chamber (JPAC). In JPAC, we also investigated the response of HOMs to NOx and seed aerosol. Using a nitrate-based chemical ionisation mass spectrometer (CI-APi-TOF), we observed the formation of HOMs in the flow reactor oxidation of benzene from the first OH attack. However, in the oxidation of toluene and naphthalene, which were injected at lower concentrations, multi-generation OH oxidation seemed to impact the HOM composition. We tested this in more detail for the benzene system in the JPAC, which allowed for studying longer residence times. The results showed that the apparent molar benzene HOM yield under our experimental conditions varied from 4.1% to 14.0%, with a strong dependence on the OH concentration, indicating that the majority of observed HOMs formed through multiple OH-oxidation steps. The composition of the identified HOMs in the mass spectrum also supported this hypothesis. By injecting only phenol into the chamber, we found that phenol oxidation cannot be solely responsible for the observed HOMs in benzene experiments. When NOx was added to the chamber, HOM composition changed and many oxygenated nitrogen-containing products were observed in CI-APi-TOF. Upon seed aerosol injection, the HOM loss rate was higher than predicted by irreversible condensation, suggesting that some undetected oxygenated intermediates also condensed onto seed aerosol, which is in line with the hypothesis that some of the HOMs were formed in multi-generation OH oxidation. Based on our results, we conclude that HOM yield and composition in aromatic systems strongly depend on OH and VOC concentration and more studies are needed to fully understand this effect on the formation of HOMs and, consequently, SOA. We also suggest that the dependence of HOM yield on chamber conditions may explain part of the variability in SOA yields reported in the literature and strongly advise monitoring HOMs in future SOA studies.Peer reviewe

Chemical characterisation of benzene oxidation products under high- and low-NOx conditions using chemical ionisation mass spectrometry

Aromatic hydrocarbons are a class of volatile organic compounds associated with anthropogenic activity and make up a significant fraction of urban volatile organic compound (VOC) emissions that contribute to the formation of secondary organic aerosol (SOA). Benzene is one of the most abundant species emitted from vehicles, biomass burning and industry. An iodide time-of-flight chemical ionisation mass spectrometer (ToF-CIMS) and nitrate ToF-CIMS were deployed at the Julich Plant Atmosphere Chamber as part of a series of experiments examining benzene oxidation by OH under high- and low-NOx conditions, where a range of organic oxidation products were detected. The nitrate scheme detects many oxidation products with high masses, ranging from intermediate volatile organic compounds (IVOCs) to extremely low volatile organic compounds (ELVOCs), including C-12 dimers. In comparison, very few species with C->= 6 and O-> 8 were detected with the iodide scheme, which detected many more IVOCs and semi-volatile organic compounds (SVOCs) but very few ELVOCs and low volatile organic compounds (LVOCs). A total of 132 and 195 CHOPeer reviewe

Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response

Background This study was performed to determine if a chemotherapy-induced apoptosis assay (MiCK) could predict the best therapy for patients with ovarian cancer. Methods A prospective, multi-institutional and blinded trial of the assay was conducted in 104 evaluable ovarian cancer patients treated with chemotherapy. The MiCK assay was performed prior to therapy, but treating physicians were not told of the results and selected treatment only on clinical criteria. Outcomes (response, time to relapse, and survival) were compared to the drug-induced apoptosis observed in the assay. Results Overall survival in primary therapy, chemotherapy naïve patients with Stage III or IV disease was longer if patients received a chemotherapy which was best in the MiCK assay, compared to shorter survival in patients who received a chemotherapy that was not the best. (p < 0.01, hazard ratio HR 0.23). Multivariate model risk ratio showed use of the best chemotherapy in the MiCK assay was the strongest predictor of overall survival (p < 0.01) in stage III or IV patients. Standard therapy with carboplatin plus paclitaxel (C + P) was not the best chemotherapy in the MiCK assay in 44% of patients. If patients received C + P and it was the best chemotherapy in the MiCK assay, they had longer survival than those patients receiving C + P when it was not the best chemotherapy in the assay (p = 0.03). Relapse-free interval in primary therapy patients was longer if patients received the best chemotherapy from the MiCK assay (p = 0.03, HR 0.52). Response rates (CR + PR) were higher if physicians used an active chemotherapy based on the MiCK assay (p = 0.03). Conclusion The MiCK assay can predict the chemotherapy associated with better outcomes in ovarian cancer patients. This study quantifies outcome benefits on which a prospective randomized trial can be developed

Increased concentrations of polychlorinated biphenyls, hexachlorobenzene, and chlordanes in mothers of men with testicular cancer.

An increasing incidence of testicular cancer has been reported from several countries in the Western world during the last decades. According to current hypothesis, testicular cancer is initiated during the fetal period, and exposure to endocrine disruptors, i.e., xenoestrogens, has been of concern. In this investigation we studied the concentrations of the sum of 38 polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene, hexachlorobenzene (HCB), and chlordanes, in 61 cases with testicular cancer and 58 age-matched controls. Furthermore, case and control mothers were also asked to participate, and 44 case mothers and 45 control mothers agreed. They were of similar age. In cases only the concentration on lipid basis of cis-nonachlordane was significantly increased, whereas case mothers showed significantly increased concentrations of the sum of PCBs, HCB, trans- and cis-nonachlordane, and the sum of chlordanes. Among case mothers the sum of PCBs yielded an odds ratio (OR) of 3.8; 95% confidence interval (CI), 1.4-10 was calculated using the median concentration for the control mothers as cutoff value. For HCB, OR = 4.4 (95% CI, 1.7-12); for trans-nonachlordane, OR = 4.1 (95% CI, 1.5-11); for cis-nonachlordane, OR = 3.1 (95% CI, 1.2-7.8); and for sum of chlordanes, OR = 1.9 (95% CI, 0.7-5.0). No consistent different risk pattern was found for seminoma or nonseminoma testicular cancer

Secondary organic aerosol reduced by mixture of atmospheric vapours

Secondary organic aerosol contributes to the atmospheric particle burden with implications for air quality and climate. Biogenic volatile organic compounds such as terpenoids emitted from plants are important secondary organic aerosol precursors with isoprene dominating the emissions of biogenic volatile organic compounds globally. However, the particle mass from isoprene oxidation is generally modest compared to that of other terpenoids. Here we show that isoprene, carbon monoxide and methane can each suppress the instantaneous mass and the overall mass yield derived from monoterpenes in mixtures of atmospheric vapours. We find that isoprene 'scavenges' hydroxyl radicals, preventing their reaction with monoterpenes, and the resulting isoprene peroxy radicals scavenge highly oxygenated monoterpene products. These effects reduce the yield of low-volatility products that would otherwise form secondary organic aerosol. Global model calculations indicate that oxidant and product scavenging can operate effectively in the real atmosphere. Thus highly reactive compounds (such as isoprene) that produce a modest amount of aerosol are not necessarily net producers of secondary organic particle mass and their oxidation in mixtures of atmospheric vapours can suppress both particle number and mass of secondary organic aerosol. We suggest that formation mechanisms of secondary organic aerosol in the atmosphere need to be considered more realistically, accounting for mechanistic interactions between the products of oxidizing precursor molecules (as is recognized to be necessary when modelling ozone production).Peer reviewe

A Four Carbon Organonitrate as a Significant Product of Secondary Isoprene Chemistry

Abstract Oxidation of isoprene by nitrate radicals (NO3) or by hydroxyl radicals (OH) under high NOx conditions forms a substantial amount of organonitrates (ONs). ONs impact NOx concentrations and consequently ozone formation while also contributing to secondary organic aerosol. Here we show that the ONs with the chemical formula C4H7NO5 are a significant fraction of isoprene-derived ONs, based on chamber experiments and ambient measurements from different sites around the globe. From chamber experiments we found that C4H7NO5 isomers contribute 5%?17% of all measured ONs formed during nighttime and constitute more than 40% of the measured ONs after further daytime oxidation. In ambient measurements C4H7NO5 isomers usually dominate both nighttime and daytime, implying a long residence time compared to C5 ONs which are removed more rapidly. We propose potential nighttime sources and secondary formation pathways, and test them using a box model with an updated isoprene oxidation scheme

Les progrès dans la réalisation de la classification quantitative de la psychopathologie

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level'' dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity'' by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach. (C) 2020 Published by Elsevier Masson SAS