Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease
TL;DR: To identify regions of high connectivity in the human cerebral cortex, a computationally efficient approach was applied to map the degree of intrinsic functional connectivity across the brain and explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD).
Abstract: Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n = 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n = 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n = 10) compared with older controls (n = 29) showed high amyloid-beta deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD.
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TL;DR: In this paper, the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI data from 1,000 subjects and a clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex.
Abstract: Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.
6,284 citations
TL;DR: This work proposes a model that relates disease stage to AD biomarkers in which Abeta biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegnerative biomarker become abnormal later, and correlate with clinical symptom severity.
Abstract: Summary Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ 42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.
3,953 citations
TL;DR: In this article, the authors studied functional brain organization in healthy adults using resting state functional connectivity MRI and proposed two novel brain wide graphs, one of 264 putative functional areas, the other a modification of voxelwise networks that eliminates potentially artificial short-distance relationships.
3,517 citations
Cites background from "Cortical Hubs Revealed by Intrinsic..."
...Such a finding need not contradict the description of posterior members of the default mode system as cortical hubs (Buckner et al., 2009), but it may alter the understanding of what it means to be a hub....
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...Standard approaches to forming whole-brain rs-fcMRI graphs often ignore this issue and define nodes as voxels (Buckner et al., 2009; Cole et al., 2010; Fransson et al., 2011; Tomasi and Volkow, 2011; van den Heuvel et al., 2008), large parcels from anatomically based brain atlases (Hartman et al....
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...It should also be noted that several studies (Buckner et al., 2009; Cole et al., 2010) have implicated the default mode system as the seat of the most prominent ‘‘hubs’’ in rs-fcMRI brain graphs....
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...Standard approaches to forming whole-brain rs-fcMRI graphs often ignore this issue and define nodes as voxels (Buckner et al., 2009; Cole et al., 2010; Fransson et al., 2011; Tomasi and Volkow, 2011; van den Heuvel et al., 2008), large parcels from anatomically based brain atlases (Hartman et al.,…...
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TL;DR: The results indicate that the CompCor method increases the sensitivity and selectivity of fcMRI analysis, and show a high degree of interscan reliability for many fc MRI measures.
Abstract: Resting state functional connectivity reveals intrinsic, spontaneous networks that elucidate the functional architecture of the human brain. However, valid statistical analysis used to identify such networks must address sources of noise in order to avoid possible confounds such as spurious correlations based on non-neuronal sources. We have developed a functional connectivity toolbox Conn (www.nitrc.org/projects/conn) that implements the component-based noise correction method (CompCor) strategy for physiological and other noise source reduction, additional removal of movement, and temporal covariates, temporal filtering and windowing of the residual blood oxygen level-dependent (BOLD) contrast signal, first-level estimation of multiple standard functional connectivity magnetic resonance imaging (fcMRI) measures, and second-level random-effect analysis for resting state as well as task-related data. Compared to methods that rely on global signal regression, the CompCor noise reduction method all...
3,388 citations
Cites background from "Cortical Hubs Revealed by Intrinsic..."
...Key words: brain connectivity; CompCor functional connectivity; intrinsic connectivity; noise; resting state...
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TL;DR: In this article, a model of the major biomarkers of Alzheimer's disease (AD) was proposed and the authors described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms.
Abstract: Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
3,197 citations
References
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TL;DR: Simple models of networks that can be tuned through this middle ground: regular networks ‘rewired’ to introduce increasing amounts of disorder are explored, finding that these systems can be highly clustered, like regular lattices, yet have small characteristic path lengths, like random graphs.
Abstract: Networks of coupled dynamical systems have been used to model biological oscillators, Josephson junction arrays, excitable media, neural networks, spatial games, genetic control networks and many other self-organizing systems. Ordinarily, the connection topology is assumed to be either completely regular or completely random. But many biological, technological and social networks lie somewhere between these two extremes. Here we explore simple models of networks that can be tuned through this middle ground: regular networks 'rewired' to introduce increasing amounts of disorder. We find that these systems can be highly clustered, like regular lattices, yet have small characteristic path lengths, like random graphs. We call them 'small-world' networks, by analogy with the small-world phenomenon (popularly known as six degrees of separation. The neural network of the worm Caenorhabditis elegans, the power grid of the western United States, and the collaboration graph of film actors are shown to be small-world networks. Models of dynamical systems with small-world coupling display enhanced signal-propagation speed, computational power, and synchronizability. In particular, infectious diseases spread more easily in small-world networks than in regular lattices.
39,297 citations
"Cortical Hubs Revealed by Intrinsic..." refers background in this paper
...Several previous analyses have demonstrated that connectivity among cortical regions is not random or proportionate across regions but rather exhibits “small world” properties, including hubs (Watts and Strogatz, 1998; Sporns et al., 2004; Achard et al., 2006; Bassett and Bullmore, 2006)....
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TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Abstract: Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
26,847 citations
"Cortical Hubs Revealed by Intrinsic..." refers methods in this paper
...All participants with AD met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria for AD (McKhann et al., 1984) and had MMSE scores 23....
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Book•
25 Nov 1994TL;DR: This paper presents mathematical representation of social networks in the social and behavioral sciences through the lens of Dyadic and Triadic Interaction Models, which describes the relationships between actor and group measures and the structure of networks.
Abstract: Part I. Introduction: Networks, Relations, and Structure: 1. Relations and networks in the social and behavioral sciences 2. Social network data: collection and application Part II. Mathematical Representations of Social Networks: 3. Notation 4. Graphs and matrixes Part III. Structural and Locational Properties: 5. Centrality, prestige, and related actor and group measures 6. Structural balance, clusterability, and transitivity 7. Cohesive subgroups 8. Affiliations, co-memberships, and overlapping subgroups Part IV. Roles and Positions: 9. Structural equivalence 10. Blockmodels 11. Relational algebras 12. Network positions and roles Part V. Dyadic and Triadic Methods: 13. Dyads 14. Triads Part VI. Statistical Dyadic Interaction Models: 15. Statistical analysis of single relational networks 16. Stochastic blockmodels and goodness-of-fit indices Part VII. Epilogue: 17. Future directions.
17,104 citations
TL;DR: The Psychophysics Toolbox is a software package that supports visual psychophysics and its routines provide an interface between a high-level interpreted language and the video display hardware.
Abstract: The Psychophysics Toolbox is a software package that supports visual psychophysics. Its routines provide an interface between a high-level interpreted language (MATLAB on the Macintosh) and the video display hardware. A set of example programs is included with the Toolbox distribution.
16,594 citations
"Cortical Hubs Revealed by Intrinsic..." refers methods in this paper
...The visual stimuli were generated on an Apple PowerBook G4 computer (Apple Computers) using Matlab (MathWorks) and the Psychophysics Toolbox extensions (Brainard, 1997)....
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TL;DR: In this article, three distinct intuitive notions of centrality are uncovered and existing measures are refined to embody these conceptions, and the implications of these measures for the experimental study of small groups are examined.
14,757 citations
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