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1.  Functional connectomics from resting-state fMRI 
Trends in cognitive sciences  2013;17(12):666-682.
Spontaneous fluctuations in activity in different parts of the brain can be used to study functional brain networks. We review the use of resting-state functional MRI for the purpose of mapping the macroscopic functional connectome. After describing MRI acquisition and image processing methods commonly used to generate data in a form amenable to connectomics network analysis, we discuss different approaches for estimating network structure from that data. Finally, we describe new possibilities resulting from the high-quality rfMRI data being generated by the Human Connectome Project, and highlight some upcoming challenges in functional connectomics.
PMCID: PMC4004765  PMID: 24238796
connectomics; resting-state fMRI; network modelling
2.  An anatomically comprehensive atlas of the adult human brain transcriptome 
Nature  2012;489(7416):391-399.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
PMCID: PMC4243026  PMID: 22996553
Neuroscience; Genetics; Genomics; Databases
3.  Resting-state fMRI in the Human Connectome Project 
NeuroImage  2013;80:144-168.
Resting-state functional magnetic resonance imaging (rfMRI) allows one to study functional connectivity in the brain by acquiring fMRI data while subjects lie inactive in the MRI scanner, and taking advantage of the fact that functionally related brain regions spontaneously co-activate. rfMRI is one of the two primary data modalities being acquired for the Human Connectome Project (the other being diffusion MRI). A key objective is to generate a detailed in vivo mapping of functional connectivity in a large cohort of healthy adults (over 1,000 subjects), and to make these datasets freely available for use by the neuroimaging community. In each subject we acquire a total of one hour of whole-brain rfMRI data at 3 Tesla, with a spatial resolution of 2×2×2mm and a temporal resolution of 0.7s, capitalizing on recent developments in slice-accelerated echo-planar imaging. We will also scan a subset of the cohort at higher field strength and resolution. In this paper we outline the work behind, and rationale for, decisions taken regarding the rfMRI data acquisition protocol and pre-processing pipelines, and present some initial results showing data quality and example functional connectivity analyses.
PMCID: PMC3720828  PMID: 23702415
4.  Distinct and Overlapping Functional Zones in the Cerebellum Defined by Resting State Functional Connectivity 
Cerebral Cortex (New York, NY)  2009;20(4):953-965.
The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral–cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.
PMCID: PMC2837094  PMID: 19684249
cerebellum; fMRI; functional connectivity; networks; resting-state
5.  Corrigendum: The quest for EEG power band correlation with ICA derived fMRI resting state networks 
PMCID: PMC4151194
erratum; combined EEG-fMRI; resting state; source modeling; ICA; ECP
6.  Advances and Pitfalls in the Analysis and Interpretation of Resting-State FMRI Data 
The last 15 years have witnessed a steady increase in the number of resting-state functional neuroimaging studies. The connectivity patterns of multiple functional, distributed, large-scale networks of brain dynamics have been recognised for their potential as useful tools in the domain of systems and other neurosciences. The application of functional connectivity methods to areas such as cognitive psychology, clinical diagnosis and treatment progression has yielded promising preliminary results, but is yet to be fully realised. This is due, in part, to an array of methodological and interpretative issues that remain to be resolved. We here present a review of the methods most commonly applied in this rapidly advancing field, such as seed-based correlation analysis and independent component analysis, along with examples of their use at the individual subject and group analysis levels and a discussion of practical and theoretical issues arising from this data ‘explosion’. We describe the similarities and differences across these varied statistical approaches to processing resting-state functional magnetic resonance imaging signals, and conclude that further technical optimisation and experimental refinement is required in order to fully delineate and characterise the gross complexity of the human neural functional architecture.
PMCID: PMC2854531  PMID: 20407579
FMRI; functional connectivity; resting-state; networks; seed-based correlations; independent component analysis
7.  Applying FSL to the FIAC Data: Model-Based and Model-Free Analysis of Voice and Sentence Repetition Priming 
Human brain mapping  2006;27(5):380-391.
This article presents results obtained from applying various tools from FSL (FMRIB Software Library) to data from the repetition priming experiment used for the HBM’05 Functional Image Analysis Contest. We present analyses from the model-based General Linear Model (GLM) tool (FEAT) and from the model-free independent component analysis tool (MELODIC). We also discuss the application of tools for the correction of image distortions prior to the statistical analysis and the utility of recent advances in functional magnetic resonance imaging (FMRI) time series modeling and inference such as the use of optimal constrained HRF basis function modeling and mixture modeling inference. The combination of hemodynamic response function (HRF) and mixture modeling, in particular, revealed that both sentence content and speaker voice priming effects occurred bilaterally along the length of the superior temporal sulcus (STS). These results suggest that both are processed in a single underlying system without any significant asymmetries for content vs. voice processing.
PMCID: PMC2653076  PMID: 16565953
functional magnetic resonance imaging (FMRI); independent component analysis (ICA); linear modeling; Functional Image Analysis Contest (FIAC)
8.  Behavioral Interpretations of Intrinsic Connectivity Networks 
Journal of cognitive neuroscience  2011;23(12):4022-4037.
An increasingly large number of neuroimaging studies have investigated functionally connected networks during rest, providing insight into human brain architecture. Assessment of the functional qualities of resting state networks has been limited by the task-independent state, which results in an inability to relate these networks to specific mental functions. However, it was recently demonstrated that similar brain networks can be extracted from resting state data and data extracted from thousands of task-based neuroimaging experiments archived in the BrainMap database. Here, we present a full functional explication of these intrinsic connectivity networks at a standard low order decomposition using a neuroinformatics approach based on the BrainMap behavioral taxonomy as well as a stratified, data-driven ordering of cognitive processes. Our results serve as a resource for functional interpretations of brain networks in resting state studies and future investigations into mental operations and the tasks that drive them.
PMCID: PMC3690655  PMID: 21671731
9.  Distinct functional networks within the cerebellum and their relation to cortical systems assessed with independent component analysis 
NeuroImage  2012;60(4):2073-2085.
Cerebellar functional circuitry has been examined in several prior studies using resting fMRI data and seed-based procedures, as well as whole-brain independent component analysis (ICA). Here, we hypothesized that ICA applied to functional data from the cerebellum exclusively would provide increased sensitivity for detecting cerebellar networks compared to previous approaches. Consistency of group-level networks was assessed in two age- and sex-matched groups of twenty-five subjects each. Cerebellum-only ICA was compared to the traditional whole-brain ICA procedure to examine the potential gain in sensitivity of the novel method. In addition to replicating a number of previously identified cerebellar networks, the current approach revealed at least one network component that was not apparent with the application of whole brain ICA. These results demonstrate the gain in sensitivity attained through specifying the cerebellum as a target structure with regard to the identification of robust and reliable networks. The use of similar procedures could be important in further expanding on previously defined patterns of cerebellar functional anatomy, as well as provide information about unique networks that have not been explored in prior work. Such information may prove crucial for understanding the cognitive and behavioral importance of the cerebellum in health and disease.
PMCID: PMC3549335  PMID: 22342804
Cerebellar networks; Functional connectivity; fcMRI; ICA
10.  An Investigation of RSN Frequency Spectra Using Ultra-Fast Generalized Inverse Imaging 
With the advancements in MRI hardware, pulse sequences and reconstruction techniques, many low TR sequences are becoming more and more popular within the functional MRI (fMRI) community. In this study, we have investigated the spectral characteristics of resting state networks (RSNs) with a newly introduced ultra fast fMRI technique, called generalized inverse imaging (GIN). The high temporal resolution of GIN (TR = 50 ms) enables to sample cardiac signals without aliasing into a separate frequency band from the BOLD fluctuations. Respiration related signal changes are, on the other hand, removed from the data without the need for external physiological recordings. We have observed that the variance over the subjects is higher than the variance over RSNs.
PMCID: PMC3632876  PMID: 23630487
GIN; resting state; respiration; dual regression; ICA; frequency analysis; fMRI BOLD; physiological noise
11.  The Quest for EEG Power Band Correlation with ICA Derived fMRI Resting State Networks 
The neuronal underpinnings of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) resting state networks (RSNs) are still unclear. To investigate the underlying mechanisms, specifically the relation to the electrophysiological signal, we used simultaneous recordings of electroencephalography (EEG) and fMRI during eyes open resting state (RS). Earlier studies using the EEG signal as independent variable show inconclusive results, possibly due to variability in the temporal correlations between RSNs and power in the low EEG frequency bands, as recently reported (Goncalves et al., 2006, 2008; Meyer et al., 2013). In this study we use three different methods including one that uses RSN timelines as independent variable to explore the temporal relationship of RSNs and EEG frequency power in eyes open RS in detail. The results of these three distinct analysis approaches support the hypothesis that the correlation between low EEG frequency power and BOLD RSNs is instable over time, at least in eyes open RS.
PMCID: PMC3691889  PMID: 23805098
combined EEG-fMRI; resting state; source modeling; RSN; ICA; ECP; IHM
12.  ICA model order selection of task co-activation networks 
Independent component analysis (ICA) has become a widely used method for extracting functional networks in the brain during rest and task. Historically, preferred ICA dimensionality has widely varied within the neuroimaging community, but typically varies between 20 and 100 components. This can be problematic when comparing results across multiple studies because of the impact ICA dimensionality has on the topology of its resultant components. Recent studies have demonstrated that ICA can be applied to peak activation coordinates archived in a large neuroimaging database (i.e., BrainMap Database) to yield whole-brain task-based co-activation networks. A strength of applying ICA to BrainMap data is that the vast amount of metadata in BrainMap can be used to quantitatively assess tasks and cognitive processes contributing to each component. In this study, we investigated the effect of model order on the distribution of functional properties across networks as a method for identifying the most informative decompositions of BrainMap-based ICA components. Our findings suggest dimensionality of 20 for low model order ICA to examine large-scale brain networks, and dimensionality of 70 to provide insight into how large-scale networks fractionate into sub-networks. We also provide a functional and organizational assessment of visual, motor, emotion, and interoceptive task co-activation networks as they fractionate from low to high model-orders.
PMCID: PMC3857551  PMID: 24339802
meta-analysis; co-activations; BrainMap; intrinsic connectivity networks; functional brain networks; functional connectivity; resting state networks; independent component analysis
13.  A Brain Network Processing the Age of Faces 
PLoS ONE  2012;7(11):e49451.
Age is one of the most salient aspects in faces and of fundamental cognitive and social relevance. Although face processing has been studied extensively, brain regions responsive to age have yet to be localized. Using evocative face morphs and fMRI, we segregate two areas extending beyond the previously established face-sensitive core network, centered on the inferior temporal sulci and angular gyri bilaterally, both of which process changes of facial age. By means of probabilistic tractography, we compare their patterns of functional activation and structural connectivity. The ventral portion of Wernicke's understudied perpendicular association fasciculus is shown to interconnect the two areas, and activation within these clusters is related to the probability of fiber connectivity between them. In addition, post-hoc age-rating competence is found to be associated with high response magnitudes in the left angular gyrus. Our results provide the first evidence that facial age has a distinct representation pattern in the posterior human brain. We propose that particular face-sensitive nodes interact with additional object-unselective quantification modules to obtain individual estimates of facial age. This brain network processing the age of faces differs from the cortical areas that have previously been linked to less developmental but instantly changeable face aspects. Our probabilistic method of associating activations with connectivity patterns reveals an exemplary link that can be used to further study, assess and quantify structure-function relationships.
PMCID: PMC3502502  PMID: 23185334
14.  Development of BOLD signal hemodynamic responses in the human brain 
Neuroimage  2012;63(2):663-673.
In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the Blood Oxygen Level Dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41 + 1 weeks), and 10 preterm infants (median PMA 34 + 4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brain's response to stimuli across the last trimester of gestation and beyond.
► First systematic characterization of the BOLD signal HRF in human neonates. ► A maturational trend in HRF morphology was identified. ► Application of empirical HRF models significantly improved neonatal fMRI analysis.
PMCID: PMC3459097  PMID: 22776460
Brain development; Neonate; Functional MRI; Hemodynamic response function
15.  Identification and characterisation of midbrain nuclei using optimised functional magnetic resonance imaging 
Neuroimage  2012;59(2-5):1230-1238.
Localising activity in the human midbrain with conventional functional MRI (fMRI) is challenging because the midbrain nuclei are small and located in an area that is prone to physiological artefacts. Here we present a replicable and automated method to improve the detection and localisation of midbrain fMRI signals. We designed a visual fMRI task that was predicted would activate the superior colliculi (SC) bilaterally. A limited number of coronal slices were scanned, orientated along the long axis of the brainstem, whilst simultaneously recording cardiac and respiratory traces. A novel anatomical registration pathway was used to optimise the localisation of the small midbrain nuclei in stereotactic space. Two additional structural scans were used to improve registration between functional and structural T1-weighted images: an echo-planar image (EPI) that matched the functional data but had whole-brain coverage, and a whole-brain T2-weighted image. This pathway was compared to conventional registration pathways, and was shown to significantly improve midbrain registration. To reduce the physiological artefacts in the functional data, we estimated and removed structured noise using a modified version of a previously described physiological noise model (PNM). Whereas a conventional analysis revealed only unilateral SC activity, the PNM analysis revealed the predicted bilateral activity. We demonstrate that these methods improve the measurement of a biologically plausible fMRI signal. Moreover they could be used to investigate the function of other midbrain nuclei.
► Functional MRI of the midbrain is difficult because it is small and prone to noise. ► Our midbrain optimised group registration allows accurate localisation of activity. ► We model and remove the structured physiological noise in the data. ► These optimisations improve the detection of a visually induced midbrain signal. ► These methods are automated and are applicable to any midbrain nuclei.
PMCID: PMC3236997  PMID: 21867762
PNM, physiological noise model; RETROICOR, retrospective image correction; fMRI; Midbrain; Superior colliculi; Physiological noise; Registration
17.  Distinct Cerebellar Contributions to Intrinsic Connectivity Networks 
Convergent data from various scientific approaches strongly implicate cerebellar systems in non-motor functions. The functional anatomy of these systems has been pieced together from disparate sources such as animal studies, lesion studies in humans, and structural and functional imaging studies in humans. To better define this distinct functional anatomy, in the current study we delineate the role of the cerebellum in several non-motor systems simultaneously and in the same subjects using resting state functional connectivity MRI. Independent component analysis (ICA) was applied to resting state data from two independent datasets to identify common cerebellar contributions to several previously identified intrinsic connectivity networks (ICNs) involved in executive control, episodic memory/self-reflection, salience detection, and sensorimotor function. We found distinct cerebellar contributions to each of these ICNs. The neocerebellum participates in: 1. the right and left executive control networks (especially crus I and II), 2. the salience network (lobule VI), and 3. the default-mode network (lobule IX). Little to no overlap was detected between these cerebellar regions and the sensorimotor cerebellum (lobules V–VI). Clusters were also located in pontine and dentate nuclei, prominent points of convergence for cerebellar input and output respectively. The results suggest that the most phylogenetically recent part of the cerebellum, particularly crus I and II make contributions to parallel cortico-cerebellar loops involved in executive control, salience detection, and episodic memory/self-reflection. The largest portions of the neocerebellum take part in the executive control network implicated in higher cognitive functions such as working memory.
PMCID: PMC2742620  PMID: 19571149
cerebellum; cerebral cortex; intrinsically connected networks; functional connectivity; resting state; cognition
18.  Whole Brain Resting-State Analysis Reveals Decreased Functional Connectivity in Major Depression 
Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within 6 months before inclusion) and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxel-wise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: (1) decreased bilateral amygdala and left anterior insula connectivity in an affective network, (2) reduced connectivity of the left frontal pole in a network associated with attention and working memory, and (3) decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or gray matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder.
PMCID: PMC2950744  PMID: 20941370
major depression; resting-state functional magnetic resonance imaging; functional connectivity; independent component analysis; amygdala
19.  Impact of Working Memory Load on fMRI Resting State Pattern in Subsequent Resting Phases 
PLoS ONE  2009;4(9):e7198.
The default-mode network (DMN) is a functional network with increasing relevance for psychiatric research, characterized by increased activation at rest and decreased activation during task performance. The degree of DMN deactivation during a cognitively demanding task depends on its difficulty. However, the relation of hemodynamic responses in the resting phase after a preceding cognitive challenge remains relatively unexplored. We test the hypothesis that the degree of activation of the DMN following cognitive challenge is influenced by the cognitive load of a preceding working-memory task.
Methodology/Principal Findings
Twenty-five healthy subjects were investigated with functional MRI at 3 Tesla while performing a working-memory task with embedded short resting phases. Data were decomposed into statistically independent spatio-temporal components using Tensor Independent Component Analysis (TICA). The DMN was selected using a template-matching procedure. The spatial map contained rest-related activations in the medial frontal cortex, ventral anterior and posterior cingulate cortex. The time course of the DMN revealed increased activation at rest after 1-back and 2-back blocks compared to the activation after a 0-back block.
We present evidence that a cognitively challenging working-memory task is followed by greater activation of the DMN than a simple letter-matching task. This might be interpreted as a functional correlate of self-evaluation and reflection of the preceding task or as relocation of cerebral resources representing recovery from high cognitive demands. This finding is highly relevant for neuroimaging studies which include resting phases in cognitive tasks as stable baseline conditions. Further studies investigating the DMN should take possible interactions of tasks and subsequent resting phases into account.
PMCID: PMC2745698  PMID: 19779619
20.  A Cross-Modal System Linking Primary Auditory and Visual Cortices 
Human brain mapping  2008;29(7):848-857.
Recent anatomical and electrophysiological evidence in primates indicates the presence of direct connections between primary auditory and primary visual cortex that constitute cross-modal systems. We examined the intrinsic functional connectivity (fcMRI) of putative primary auditory cortex in 32 young adults during resting state scanning. We found that the medial Heschl’s gyrus was strongly coupled, in particular, to visual cortex along the anterior banks of the calcarine fissure. This observation was confirmed using novel group-level, tensor-based independent components analysis. fcMRI analysis revealed that although overall coupling between the auditory and visual cortex was significantly reduced when subjects performed a visual perception task, coupling between the anterior calcarine cortex and auditory cortex was not disrupted. These results suggest that primary auditory cortex has a functionally distinct relationship with the anterior visual cortex, which is known to represent the peripheral visual field. Our study provides novel, fcMRI-based, support for a neural system involving low-level auditory and visual cortices.
PMCID: PMC2605422  PMID: 18412133
functional connectivity; cross-modal; multisensory; primary auditory cortex; primary visual cortex
21.  Investigations into resting-state connectivity using independent component analysis 
Inferring resting-state connectivity patterns from functional magnetic resonance imaging (fMRI) data is a challenging task for any analytical technique. In this paper, we review a probabilistic independent component analysis (PICA) approach, optimized for the analysis of fMRI data, and discuss the role which this exploratory technique can take in scientific investigations into the structure of these effects. We apply PICA to fMRI data acquired at rest, in order to characterize the spatio-temporal structure of such data, and demonstrate that this is an effective and robust tool for the identification of low-frequency resting-state patterns from data acquired at various different spatial and temporal resolutions. We show that these networks exhibit high spatial consistency across subjects and closely resemble discrete cortical functional networks such as visual cortical areas or sensory–motor cortex.
PMCID: PMC1854918  PMID: 16087444
functional magnetic resonance imaging; brain connectivity; resting-state fluctuations; independent component analysis

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