Since its inception over twenty years ago, the field of functional magnetic resonance imaging (fMRI) has grown in usage, sophistication, range of applications, and impact. After twenty years, it's useful to briefly look back as well as forward - to size up just how far we have come and speculate just how far we may go. This is an introduction to the special issue of

The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease.

It has recently been reported (Van Dijk et al., 2011) that in-scanner head motion can have a substantial impact on MRI measurements of resting-state functional connectivity. This finding may be of particular relevance for studies of neurodevelopment in youth, confounding analyses to the extent that motion and subject age are related. Furthermore, while Van Dijk et al. demonstrated the effect of motion on seed-based connectivity analyses, it is not known how motion impacts other common measures of connectivity. Here we expand on the findings of Van Dijk et al. by examining the effect of motion on multiple types of resting-state connectivity analyses in a large sample of children and adolescents (n=456). Following replication of the effect of motion on seed-based analyses, we examine the influence of motion on graphical measures of network modularity, dual-regression of independent component analysis, as well as the amplitude and fractional amplitude of low frequency fluctuation. In the entire sample, subject age was highly related to motion. Using a subsample where age and motion were unrelated, we demonstrate that motion has marked effects on connectivity in every analysis examined. While subject age was associated with increased within-network connectivity even when motion was accounted for, controlling for motion substantially attenuated the strength of this relationship. The results demonstrate the pervasive influence of motion on multiple types functional connectivity analysis, and underline the importance of accounting for motion in studies of neurodevelopment.

Functional connectivity MRI (fcMRI) has been widely applied to explore group and individual differences. A confounding factor is head motion. Children move more than adults, older adults more than younger adults, and patients more than controls. Head motion varies considerably among individuals within the same population. Here we explored the influence of head motion on fcMRI estimates. Mean head displacement, maximum head displacement, the number of micro movements (>0.1 mm), and head rotation were estimated in 1000 healthy, young adult subjects each scanned for two resting-state runs on matched 3T scanners. The majority of fcMRI variation across subjects was not linked to head motion. However, head motion had significant, systematic effects on fcMRI network measures. Head motion was associated with decreased functional coupling in the default and frontoparietal control networks--two networks characterized by coupling among distributed regions of association cortex. Other network measures increased with motion including estimates of local functional coupling and coupling between left and right motor regions--a region pair sometimes used as a control in studies to establish specificity. Comparisons between groups of individuals with subtly different levels of head motion yielded difference maps that could be mistaken for neuronal effects in other contexts. These effects are important to consider when interpreting variation between groups and across individuals.

Functional connectomics is one of the most rapidly expanding areas of neuroimaging research. Yet, concerns remain regarding the use of resting-state fMRI (R-fMRI) to characterize inter-individual variation in the functional connectome. In particular, recent findings that

Concerns regarding reproducibility of resting-state functional magnetic resonance imaging (R-fMRI) findings have been raised. Little is known about how to operationally define R-fMRI reproducibility and to what extent it is affected by multiple comparison correction strategies and sample size. We comprehensively assessed two aspects of reproducibility, test-retest reliability and replicability, on widely used R-fMRI metrics in both between-subject contrasts of sex differences and within-subject comparisons of eyes-open and eyes-closed (EOEC) conditions. We noted permutation test with Threshold-Free Cluster Enhancement (TFCE), a strict multiple comparison correction strategy, reached the best balance between family-wise error rate (under 5%) and test-retest reliability/replicability (e.g., 0.68 for test-retest reliability and 0.25 for replicability of amplitude of low-frequency fluctuations (ALFF) for between-subject sex differences, 0.49 for replicability of ALFF for within-subject EOEC differences). Although R-fMRI indices attained moderate reliabilities, they replicated poorly in distinct datasets (replicability < 0.3 for between-subject sex differences, < 0.5 for within-subject EOEC differences). By randomly drawing different sample sizes from a single site, we found reliability, sensitivity and positive predictive value (PPV) rose as sample size increased. Small sample sizes (e.g., < 80 [40 per group]) not only minimized power (sensitivity < 2%), but also decreased the likelihood that significant results reflect

As researchers increase their efforts to characterize variations in the functional connectome across studies and individuals, concerns about the many sources of nuisance variation present and their impact on resting state fMRI (R-fMRI) measures continue to grow. Although substantial within-site variation can exist efforts to aggregate data across multiple sites such as the 1000 Functional Connectomes Project (FCP) and International Neuroimaging Data-sharing Initiative (INDI) datasets amplify these concerns. The present work draws upon standardization approaches commonly used in the microarray gene expression literature, and to a lesser extent recent imaging studies, and compares them with respect to their impact on relationships between common R-fMRI measures and nuisance variables (e.g., imaging site, motion), as well as phenotypic variables of interest (age, sex). Standardization approaches differed with regard to whether they were applied post-hoc vs. during pre-processing, and at the individual vs. group level; additionally they varied in whether they addressed additive effects vs. additive + multiplicative effects, and were parametric vs. non-parametric. While all standardization approaches were effective at reducing undesirable relationships with nuisance variables, post-hoc approaches were generally more effective than global signal regression (GSR). Across approaches, correction for additive effects (global mean) appeared to be more important than for multiplicative effects (global SD) for all R-fMRI measures, with the exception of amplitude of low frequency fluctuations (ALFF). Group-level post-hoc standardizations for mean-centering and variance-standardization were found to be advantageous in their ability to avoid the introduction of artifactual relationships with standardization parameters; though results between individual and group-level post-hoc approaches were highly similar overall. While post-hoc standardization procedures drastically increased test-retest (TRT) reliability for ALFF, modest reductions were observed for other measures after post-hoc standardizations a phenomena likely attributable to the separation of voxel-wise from global differences among subjects (global mean and SD demonstrated moderate TRT reliability for these measures). Finally, the present work calls into question previous observations of increased anatomical specificity for GSR over mean centering, and draws attention to the near equivalence of global and gray matter signal regression. (C) 2013 Elsevier Inc.

Resting-state functional magnetic resonance imaging (fMRI) has attracted more and more attention because of its effectiveness, simplicity and non-invasiveness in exploration of the intrinsic functional architecture of the human brain. However, user-friendly toolbox for

Brain imaging efforts are being increasingly devoted to decode the functioning of the human brain. Among neuroimaging techniques, resting-state fMRI (R-fMRI) is currently expanding exponentially. Beyond the general neuroimaging analysis packages (e.g., SPM, AFNI and FSL), REST and DPARSF were developed to meet the increasing need of user-friendly toolboxes for R-fMRI data processing. To address recently identified methodological challenges of R-fMRI, we introduce the newly developed toolbox, DPABI, which was evolved from REST and DPARSF. DPABI incorporates recent research advances on head motion control and measurement standardization, thus allowing users to evaluate results using stringent control strategies. DPABI also emphasizes test-retest reliability and quality control of data processing. Furthermore, DPABI provides a user-friendly pipeline analysis toolkit for rat/monkey R-fMRI data analysis to reflect the rapid advances in animal imaging. In addition, DPABI includes preprocessing modules for task-based fMRI, voxel-based morphometry analysis, statistical analysis and results viewing. DPABI is designed to make data analysis require fewer manual operations, be less time-consuming, have a lower skill requirement, a smaller risk of inadvertent mistakes, and be more comparable across studies. We anticipate this open-source toolbox will assist novices and expert users alike and continue to support advancing R-fMRI methodology and its application to clinical translational studies.

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. FINDINGS: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3.9% (95% uncertainty interval [UI] 3.1-4.6) from 1990 to 2017; however, the all-age YLD rate increased by 7.2% (6.0-8.4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7.9% (6.6-9.2) for males and 6.5% (5.4-7.7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs s1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). INTERPRETATION: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury. FUNDING: Bill & Melinda Gates Foundation.

Data sharing is increasingly recommended as a means of accelerating science by facilitating collaboration, transparency, and reproducibility. While few oppose data sharing philosophically, a range of barriers deter most researchers from implementing it in practice. To justify the significant effort required for sharing data, funding agencies, institutions, and investigators need clear evidence of benefit. Here, using the International Neuroimaging Data-sharing Initiative, we present a case study that provides direct evidence of the impact of open sharing on brain imaging data use and resulting peer-reviewed publications. We demonstrate that openly shared data can increase the scale of scientific studies conducted by data contributors, and can recruit scientists from a broader range of disciplines. These findings dispel the myth that scientific findings using shared data cannot be published in high-impact journals, suggest the transformative power of data sharing for accelerating science, and underscore the need for implementing data sharing universally.

Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.