Identifying canonical and replicable multi-scale intrinsic connectivity networks in 100k+ resting-state fMRI datasets.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

A method for estimating and characterizing explicitly nonlinear dynamic functional network connectivity in resting-state fMRI data.

The past 10 years have seen an explosion of approaches that focus on the study of time-resolved change in functional connectivity (FC). FC characterization among networks at a whole-brain level is frequently termed functional network connectivity (FNC). Time-resolved or dynamic functional network connectivity (dFNC) focuses on the estimation of transient, recurring, whole-brain patterns of FNC. While most approaches in this area have attempted to capture dynamic linear correlation, we are particularly interested in whether explicitly nonlinear relationships, above and beyond linear, are present and contain unique information. This study thus proposes an approach to assess explicitly nonlinear dynamic functional network connectivity (EN dFNC) derived from the relationship among independent component analysis time courses. Linear relationships were removed at each time point to evaluate, typically ignored, explicitly nonlinear dFNC using normalized mutual information (NMI). Simulations showed the proposed method estimated explicitly nonlinearity over time, even within relatively short windows of data. We then, applied our approach on 151 schizophrenia patients, and 163 healthy controls fMRI data and found three unique, highly structured, mostly long-range, functional states that also showed significant group differences. In particular, explicitly nonlinear relationships tend to be more widespread than linear ones. Results also highlighted a state with long range connections to the visual domain, which were significantly reduced in schizophrenia. Overall, this work suggests that quantifying EN dFNC may provide a complementary and potentially valuable tool for studying brain function by exposing relevant variation that is typically ignored.

Resting Hypoconnectivity of Theoretically Defined Addiction Networks during Early Abstinence Predicts Subsequent Relapse in Alcohol Use Disorder.

Theoretical models of addiction suggest that alterations in addiction domains including incentive salience, negative emotionality, and executive control lead to relapse in alcohol use disorder (AUD). To determine whether the functional organization of neural networks underlying these domains predict subsequent relapse, we generated theoretically defined addiction networks. We collected resting functional magnetic resonance imaging data from 45 individuals with AUD during early abstinence (number of days abstinent M = 25.40, SD = 16.51) and calculated the degree of resting-state functional connectivity (RSFC) within these networks. Regression analyses determined whether the RSFC strength in domain-defined addiction networks measured during early abstinence predicted subsequent relapse (dichotomous or continuous relapse metrics). RSFC within each addiction network measured during early abstinence was significantly lower in those that relapsed (vs. abstained) and predicted subsequent time to relapse. Lower incentive salience RSFC during early abstinence increased the odds of relapsing. Neither RSFC in a control network nor clinical self-report measures predicted relapse. The association between low incentive salience RSFC and faster relapse highlights the need to design timely interventions that enhance RSFC in AUD individuals at risk of relapsing faster.

Exploratory study of how Cognitive Multisensory Rehabilitation restores parietal operculum connectivity and improves upper limb movements in chronic stroke.

Cognitive Multisensory Rehabilitation (CMR) is a promising therapy for upper limb recovery in stroke, but the brain mechanisms are unknown. We previously demonstrated that the parietal operculum (parts OP1/OP4) is activated with CMR exercises. In this exploratory study, we assessed the baseline difference between OP1/OP4 functional connectivity (FC) at rest in stroke versus healthy adults to then explore whether CMR affects OP1/OP4 connectivity and sensorimotor recovery after stroke. We recruited 8 adults with chronic stroke and left hemiplegia/paresis and 22 healthy adults. Resting-state FC with the OP1/OP4 region-of-interest in the affected hemisphere was analysed before and after 6 weeks of CMR. We evaluated sensorimotor function and activities of daily life pre- and post-CMR, and at 1-year post-CMR. At baseline, we found decreased FC between the right OP1/OP4 and 34 areas distributed across all lobes in stroke versus healthy adults. After CMR, only four areas had decreased FC compared to healthy adults. Compared to baseline (pre-CMR), participants improved on motor function (MESUPES arm p = 0.02; MESUPES hand p = 0.03; MESUPES total score p = 0.006); on stereognosis (p = 0.03); and on the Frenchay Activities Index (p = 0.03) at post-CMR and at 1-year follow-up. These results suggest enhanced sensorimotor recovery post-stroke after CMR. Our results justify larger-scale studies.

Resting-state thalamic dysconnectivity in schizophrenia and relationships with symptoms.

BACKGROUND: Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities. METHOD: Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined. RESULTS: HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior. CONCLUSIONS: Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia.

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical-subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.

A VARIATIONAL MODEL FOR DENOISING HIGH ANGULAR RESOLUTION DIFFUSION IMAGING.

The presence of noise in High Angular Resolution Diffusion Imaging (HARDI) data of the brain can limit the accuracy with which fiber pathways of the brain can be extracted. In this work, we present a variational model to denoise HARDI data corrupted by Rician noise. Numerical experiments are performed on three types of data: 2D synthetic data, 3D diffusion-weighted Magnetic Resonance Imaging (DW-MRI) data of a hardware phantom containing synthetic fibers, and 3D real HARDI brain data. Experiments show that our model is effective for denoising HARDI-type data while preserving important aspects of the fiber pathways such as fractional anisotropy and the orientation distribution functions.

Birth characteristics and childhood carcinomas.

BACKGROUND: Carcinomas in children are rare and have not been well studied. METHODS: We conducted a population-based case-control study and examined associations between birth characteristics and childhood carcinomas diagnosed from 28 days to 14 years during 1980-2004 using pooled data from five states (NY, WA, MN, TX, and CA) that linked their birth and cancer registries. The pooled data set contained 57,966 controls and 475 carcinoma cases, including 159 thyroid and 126 malignant melanoma cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: White compared with 'other' race was positively associated with melanoma (OR=3.22, 95% CI 1.33-8.33). Older maternal age increased the risk for melanoma (OR(per 5-year age increase)=1.20, 95% CI 1.00-1.44), whereas paternal age increased the risk for any carcinoma (OR=1.10(per 5-year age increase), 95% CI 1.01-1.20) and thyroid carcinoma (OR(per 5-year age increase)=1.16, 95% CI 1.01-1.33). Gestational age < 37 vs 37-42 weeks increased the risk for thyroid carcinoma (OR=1.87, 95% CI 1.07-3.27). Plurality, birth weight, and birth order were not significantly associated with childhood carcinomas. CONCLUSION: This exploratory study indicates that some birth characteristics including older parental age and low gestational age may be related to childhood carcinoma aetiology.

Association between wearing a personal floatation device and death by drowning among recreational boaters: a matched cohort analysis of United States Coast Guard data.

OBJECTIVE: To estimate the association between wearing a personal floatation device (PFD) and death by drowning among recreational boaters. DESIGN: Matched cohort study analysis of Coast Guard data. SETTING: United States. SUBJECTS: Recreational boaters during 2000-2006. MAIN OUTCOME MEASURES: Risk ratio (RR) for drowning death comparing boaters wearing a PFD with boaters not wearing a PFD. RESULTS: Approximately 4915 boater records from 1809 vessels may have been eligible for our study, but because of missing records and other problems, the analysis was restricted to 1597 boaters in 625 vessels with 878 drowning deaths. The adjusted RR was 0.51 (95% CI 0.35 to 0.74). CONCLUSIONS: If the estimated association is causal, wearing a PFD may potentially prevent one in two drowning deaths among recreational boaters. However, this estimate may be biased because many vessels had to be excluded from the analysis.

Parental educational attainment as an indicator of socioeconomic status and risk of childhood cancers.

BACKGROUND: Little has been reported on socioeconomic (SES) patterns of risk for most forms of childhood cancer. METHODS: Population-based case-control data from epidemiological studies of childhood cancer conducted in five US states were pooled and associations of maternal, paternal and household educational attainment with childhood cancers were analysed. Odds ratios (ORs) and 95% confidence intervals were estimated using logistic regression, controlling for confounders. RESULTS: Although there was no association with parental education for the majority of cancers evaluated, there was an indication of a positive association with lower education for Hodgkin's and Burkitt's lymphoma and Wilm's tumour, with the ORs ranging from 1.5 to >3.0 times that of more educated parents. A possible protective effect was seen for lower parental education and astrocytoma and hepatoblastoma, with ORs reduced by 30 to 40%. CONCLUSIONS: These study results should be viewed as exploratory because of the broad nature of the SES assessment, but they give some indication that childhood cancer studies might benefit from a more thorough assessment of SES.

Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype.

BACKGROUND: Little is known about risk factors for childhood rhabdomyosarcoma (RMS) and the histology-specific details are rare. METHODS: Case-control studies formed by linking cancer and birth registries of California, Minnesota, New York, Texas and Washington, which included 583 RMS cases (363 embryonal and 85 alveolar RMS) and 57 966 randomly selected control subjects, were analysed using logistic regression. The associations of RMS (overall, and based on embryonal or alveolar histology) with birth weight across five 500 g categories (from 2000 to 4500 g) were examined using normal birth weight (2500-3999 g) as a reference. Large (>90th percentile) and small (<10th percentile) size for gestational age were calculated based on birth weight distributions in controls and were similarly examined. RESULTS: High birth weight increased the risk of embryonal RMS and RMS overall. Each 500 g increase in birth weight increased the risk of embryonal RMS (odds ratio (OR)=1.27, 95% confidence interval (CI)=1.14-1.42) and RMS overall (OR=1.18, 95% CI=1.09-1.29). Large size for gestational age also significantly increased the risk of embryonal RMS (OR=1.42, 95% CI=1.03-1.96). CONCLUSIONS: These data suggest a positive association between accelerated in utero growth and embryonal RMS, but not alveolar RMS. These results warrant cautious interpretation owing to the small number of alveolar RMS cases.

Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy.

The challenges of appropriate drug dosing in patients with renal failure requiring renal replacement therapy (RRT) have been exacerbated by recent trends in both RRT technology and practices. Nearly all these changes have resulted in augmented drug clearance, making most existing RRT drug dosing recommendations obsolete. Many barriers exist to conducting research to update our knowledge of appropriate drug dosing in the context of contemporary RRT. Recommendations on how this research could be conducted, including the use of in vitro techniques, are offered here.

Measurement of angular distributions of Drell-Yan dimuons in p+p interactions at 800 GeV/c.

We report a measurement of the angular distributions of Drell-Yan dimuons produced using an 800 GeV/c proton beam on a hydrogen target. The polar and azimuthal angular distribution parameters have been extracted over the kinematic range 4.5

Ertapenem clearance during modeled continuous renal replacement therapy.

PURPOSE: To determine ertapenem transmembrane clearance (CLtm) during continuous renal replacement therapy (CRRT) using a validated in vitro model. METHODS: Ertapenem clearance during continuous hemofiltration and hemodialysis was assessed with AN69 and polysulfone hemodiafilters at 4 dialysate (Qd) and ultrafiltration rates (Quf): 1, 2, 3, and 6 l/hour. Blood and dialysate samples were collected at each flow rate and assayed for urea (control solute) and ertapenem concentrations. The experiment was repeated 5 times for each hemodiafilter type. Ertapenem and urea sieving coefficient (SC) and saturation coefficient (SA) were assessed, and CLtm calculated. RESULTS: In continuous hemofiltration mode, urea and ertapenem SC ranged from 1.00 to 1.19 at all Quf and did not differ between hemodiafilter types. Consequently, convective CLtm also did not differ between hemodiafilters. In continuous dialysis mode, urea Cltm did not differ between hemodiafilter types at any Qd. However, ertapenem SA and CLtm were significantly different between hemodiafilter types at Qd 6l/hour (p<0.001). As Qd increased, mean +/- SD AN69 SA declined significantly from 0.87 +/- 0.12 at Qd 1 l/hour to 0.45 +/- 0.02 at Qd 6 l/hour (p<0.001). Ertapenem SA did not differ at any Qd with the polysulfone hemodiafilter (range 0.71-0.80). CONCLUSION: Ertapenem was cleared substantially in these in vitro CRRT models. However, our findings illustrate discordance between our observed SC and SA and the published unbound fraction of ertapenem. This finding has been reported with many other drugs, including carbapenem antibiotics. If in vivo studies corroborate our SA and SC findings, dosage adjustment for patients receiving CRRT will be required.

Randomized controlled trial of ionization and photoelectric smoke alarm functionality.

OBJECTIVE: To compare functionality, reasons for non-function, and nuisance alarm levels of two common types of smoke alarms after installation in low- to mid-level income households in King County, Washington. METHODS: Randomized controlled trial of 761 households. An ionization or photoelectric smoke alarm was installed between June 1, 2000 and July 31, 2002. Main outcome measures were: percentage of study alarms that were working, observed reasons for non-functional status, and self-reported frequency of nuisance alarms at 9 and 15 months of follow-up. RESULTS: At 9 months after installation, 20% of ionization, vs 5% of photoelectric alarms were non-functional, a difference that persisted at 15 months, with the most common reasons for both types being a disconnected or absent battery. The risk ratio for ionization, relative to photoelectric alarms, being non-functional or removed was 2.7 (95% CI 1.8 to 4.1) at 15 months of follow-up. These findings were not altered by educational level, or the presence of smokers, children <5 years, or adults > or =65 years. CONCLUSIONS: Burn prevention efforts are geared towards increasing smoke alarm ownership and improving maintenance of functional status. Results suggest that the selective use of photoelectric alarms by fire injury prevention programs or consumers may provide longer-term protection in similar populations. Designing smoke alarms that minimize nuisance alarming may also result in longer term functionality.

Measurement of Upsilon production for p + p and p + d interactions at 800 GeV/c.

We report a high statistics measurement of Upsilon production with an 800 GeV/c proton beam on hydrogen and deuterium targets. The dominance of the gluon-gluon fusion process for Upsilon production at this energy implies that the cross section ratio, sigma(p+d-->Upsilon)/2sigma(p+p-->Upsilon), is sensitive to the gluon content in the neutron relative to that in the proton. Over the kinematic region 0

Measurement of angular distributions of Drell-Yan dimuons in p+d interactions at 800 GeV/c.

We report a measurement of the angular distributions of Drell-Yan dimuons produced using an 800 GeV/c proton beam on a deuterium target. The muon angular distributions in the dilepton rest frame have been measured over the kinematic range 4.5

Beauty product-related exposures and childhood brain tumors in seven countries: results from the SEARCH International Brain Tumor Study.

Data from 1218 cases of childhood brain tumors (CBT) diagnosed between 1976 and 1994 and 2223 matched controls from the general population were included in an analysis of maternal beauty product exposure and beauty-related employment in 9 centers in 7 countries. A 50% increased odds ratio (OR) [95% confidence interval (CI) = 1.0-2.1] for CBT was observed among children of mothers who were exposed via personal use of and/or possible ambient contact with beauty products during the 5 years preceding the index child's birth compared with children of mothers never exposed to beauty products during this time period. Overall maternal personal use of hair-coloring agents in the month before or during the pregnancy of the index child's birth was not associated with CBT (OR = 1.0, CI = 0.83-1.3) or with astroglial (OR = 1.1, CI = 0.85-1.4), PNET (OR = 1.0, CI = 0.71-1.5) and other glial subtypes (OR = 1.0, CI = 0.62-1.0). Similarly, no statistically increased ORs or discernable pattern of risk estimates were observed for period of use or for number of applications per year for maternal personal use of hair-coloring agents overall or by histologic type. Among children born on or after 1980, increased ORs for CBT were associated with maternal non-work-related exposure to any beauty products (OR = 2.6, CI = 1.2-5.9), hair-dyes (OR = 11, CI = 1.2-90), and hair sprays (OR = 3.4, CI = 1.0-11). No overall increased OR for CBT was observed among children of mothers employed in beauty-related jobs during the 5 years preceding the index child's birth compared with those who reported no beauty-related employment. In general, other specific beauty product-related exposures were not associated with increased ORs for CBT. Data from our study provide little evidence of an increased risk for CBT with mothers' exposures to beauty products.