Probing resting-state functional connectivity in the infant brain: methods and potentiality

Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Moreover, potent postnatal brain plasticity engenders increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Recently, resting-state functional magnetic resonance imaging (fMRI) emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Its application has expanded to infant populations in the past decade, providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal/ disease states. However, rapid extension of the resting-state technique to infant populations leaves many methodological issues need to be resolved prior to standardization of the technique. The purpose of this thesis is to describe a protocol for intrinsic functional connectivity analysis, and extraction of resting-state networks in infants <12 months of age using the data-driven approach independent component analysis (ICA). To begin, we review the evolution of resting-state fMRI application in infant populations, including the biological premise for neural networks. Next, we present a protocol designed such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature. Presented protocol provides detailed, albeit basic framework for RSN analysis, with interwoven discussion of basic theory behind each technique, as well as the rationale behind selecting parameters. The overarching goal is to catalyze efforts towards development of robust, infant-specific acquisition and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used. Finally, we review the literature, current methodological challenges and potential future directions for the field of infant resting-state fMRI

Semiparametric Estimation of Task-Based Dynamic Functional Connectivity on the Population Level

Dynamic functional connectivity (dFC) estimates time-dependent associations between pairs of brain region time series as typically acquired during functional MRI. dFC changes are most commonly quantified by pairwise correlation coefficients between the time series within a sliding window. Here, we applied a recently developed bootstrap-based technique (Kudela et al., 2017) to robustly estimate subject-level dFC and its confidence intervals in a task-based fMRI study (24 subjects who tasted their most frequently consumed beer and Gatorade as an appetitive control). We then combined information across subjects and scans utilizing semiparametric mixed models to obtain a group-level dFC estimate for each pair of brain regions, flavor, and the difference between flavors. The proposed approach relies on the estimated group-level dFC accounting for complex correlation structures of the fMRI data, multiple repeated observations per subject, experimental design, and subject-specific variability. It also provides condition-specific dFC and confidence intervals for the whole brain at the group level. As a summary dFC metric, we used the proportion of time when the estimated associations were either significantly positive or negative. For both flavors, our fully-data driven approach yielded regional associations that reflected known, biologically meaningful brain organization as shown in prior work, as well as closely resembled resting state networks (RSNs). Specifically, beer flavor-potentiated associations were detected between several reward-related regions, including the right ventral striatum (VST), lateral orbitofrontal cortex, and ventral anterior insular cortex (vAIC). The enhancement of right VST-vAIC association by a taste of beer independently validated the main activation-based finding (Oberlin et al., 2016). Most notably, our novel dFC methodology uncovered numerous associations undetected by the traditional static FC analysis. The data-driven, novel dFC methodology presented here can be used for a wide range of task-based fMRI designs to estimate the dFC at multiple levels-group-, individual-, and task-specific, utilizing a combination of well-established statistical methods

Quality data assessment and improvement in pre-processing pipeline to minimize impact of spurious signals in functional magnetic imaging (fMRI)

In the recent years, the field of quality data assessment and signal denoising in functional magnetic resonance imaging (fMRI) is rapidly evolving and the identification and reduction of spurious signal with pre-processing pipeline is one of the most discussed topic. In particular, subject motion or physiological signals, such as respiratory or/and cardiac pulsatility, were showed to introduce false-positive activations in subsequent statistical analyses. Different measures for the evaluation of the impact of motion related artefacts, such as frame-wise displacement and root mean square of movement parameters, and the reduction of these artefacts with different approaches, such as linear regression of nuisance signals and scrubbing or censoring procedure, were introduced. However, we identify two main drawbacks: i) the different measures used for the evaluation of motion artefacts were based on user-dependent thresholds, and ii) each study described and applied their own pre-processing pipeline. Few studies analysed the effect of these different pipelines on subsequent analyses methods in task-based fMRI.The first aim of the study is to obtain a tool for motion fMRI data assessment, based on auto-calibrated procedures, to detect outlier subjects and outliers volumes, targeted on each investigated sample to ensure homogeneity of data for motion. The second aim is to compare the impact of different pre-processing pipelines on task-based fMRI using GLM based on recent advances in resting state fMRI preprocessing pipelines. Different output measures based on signal variability and task strength were used for the assessment

Neural, electrophysiological and anatomical basis of brain-network variability and its characteristic changes in mental disorders

Functional brain networks demonstrate significant temporal variability and dynamic reconfiguration even in the resting state. Currently, most studies investigate temporal variability of brain networks at the scale of single (micro) or whole-brain (macro) connectivity. However, the mechanism underlying time-varying properties remains unclear, as the coupling between brain network variability and neural activity is not readily apparent when analysed at either micro or macroscales. We propose an intermediate 15 (meso) scale analysis and characterize temporal variability of the functional architecture associated with a particular region. This yields a topography of variability that reflects the whole-brain and, most importantly, creates an analytical framework to establish the fundamental relationship between variability of regional functional architecture and its neural activity or structural connectivity. We find that temporal variability reflects the dynamical reconfiguration of a brain region into distinct functional modules at different times and may be indicative of brain flexibility and adaptability. Primary and unimodal sensory-motor cortices demon- 20 strate low temporal variability, while transmodal areas, including heteromodal association areas and limbic system, demonstrate the high variability. In particular, regions with highest variability such as hippocampus/parahippocampus, inferior and middle temporal gyrus, olfactory gyrus and caudate are all related to learning, suggesting that the temporal variability may indicate the level of brain adaptability. With simultaneously recorded electroencephalography/functional magnetic resonance imaging and functional magnetic resonance imaging/diffusion tensor imaging data, we also find that variability of regional functional architec- 25 ture is modulated by local blood oxygen level-dependent activity and a-band oscillation, and is governed by the ratio of intra- to inter-community structural connectivity. Application of the mesoscale variability measure to multicentre datasets of three mental disorders and matched controls involving 1180 subjects reveals that those regions demonstrating extreme, i.e. highest/lowest variability in controls are most liable to change in mental disorders. Specifically, we draw attention to the identification of diametrically opposing patterns of variability changes between schizophrenia and attention deficit hyperactivity disorder/autism. 30 Regions of the default-mode network demonstrate lower variability in patients with schizophrenia, but high variability in patients with autism/attention deficit hyperactivity disorder, compared with respective controls. In contrast, subcortical regions, especially the thalamus, show higher variability in schizophrenia patients, but lower variability in patients with attention deficit hyperactivity disorder. The changes in variability of these regions are also closely related to symptom scores. Our work provides insights into the dynamic organization of the resting brain and how it changes in brain disorders. The nodal variability measure may also be 35 potentially useful as a predictor for learning and neural rehabilitation

Disrupted network architecture of the resting brain in attention‐deficit/hyperactivity disorder

Background Attention‐deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders of childhood. Neuroimaging investigations of ADHD have traditionally sought to detect localized abnormalities in discrete brain regions. Recent years, however, have seen the emergence of complementary lines of investigation into distributed connectivity disturbances in ADHD. Current models emphasize abnormal relationships between default network—involved in internally directed mentation and lapses of attention—and task positive networks, especially ventral attention network. However, studies that comprehensively investigate interrelationships between large‐scale networks in ADHD remain relatively rare. Methods Resting state functional magnetic resonance imaging scans were obtained from 757 participants at seven sites in the ADHD‐200 multisite sample. Functional connectomes were generated for each subject, and interrelationships between seven large‐scale brain networks were examined with network contingency analysis. Results ADHD brains exhibited altered resting state connectivity between default network and ventral attention network [ P  < 0.0001, false discovery rate (FDR)‐corrected], including prominent increased connectivity (more specifically, diminished anticorrelation) between posterior cingulate cortex in default network and right anterior insula and supplementary motor area in ventral attention network. There was distributed hypoconnectivity within default network ( P  = 0.009, FDR‐corrected), and this network also exhibited significant alterations in its interconnections with several other large‐scale networks. Additionally, there was pronounced right lateralization of aberrant default network connections. Conclusions Consistent with existing theoretical models, these results provide evidence that default network‐ventral attention network interconnections are a key locus of dysfunction in ADHD. Moreover, these findings contribute to growing evidence that distributed dysconnectivity within and between large‐scale networks is present in ADHD. Hum Brain Mapp 35:4693–4705, 2014 . © 2014 Wiley Periodicals, Inc .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107992/1/hbm22504.pd

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)—a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7–64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies