Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease

Department of Psychology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2009; 29(6):1860-73. DOI: 10.1523/JNEUROSCI.5062-08.2009
Source: PubMed


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.

Download full-text


Available from: Jorge Sepulcre,
56 Reads
  • Source
    • "To avoid a priori selection of specific regions of interest (ROIs), we used a data-driven approach to map the wFCS at the voxel level and identified the regions that showed aberrant FCS in the TS patients. Similar approaches have been applied to study mental dysfunction (Gotts et al. 2012; Wang et al. 2014) and to search for connectivity hubs within the brain (Buckner et al. 2009; Tomasi and Volkow 2010). A set of regions including the bilateral IPS, ANG, cuneus, and cerebellum showed reduced wFCS in the TS patients compared with the HCs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Turner syndrome (TS), a disorder caused by the congenital absence of one of the 2 X chromosomes in female humans, provides a valuable human "knockout model" for studying the functions of the X chromosome. At present, it remains unknown whether and how the loss of the X chromosome influences intrinsic functional connectivity (FC), a fundamental phenotype of the human brain. To address this, we performed resting-state functional magnetic resonance imaging and specific cognitive assessments on 22 TS patients and 17 age-matched control girls. A novel data-driven approach was applied to identify the disrupted patterns of intrinsic FC in TS. The TS girls exhibited significantly reduced whole-brain FC strength within the bilateral postcentral gyrus/intraparietal sulcus, angular gyrus, and cuneus and the right cerebellum. Furthermore, a specific functional subnetwork was identified in which the intrinsic FC between nodes was mostly reduced in TS patients. Particularly, this subnetwork is composed of 3 functional modules, and the disruption of intrinsic FC within one of these modules was associated with the deficits of TS patients in math-related cognition. Taken together, these findings provide novel insight into how the X chromosome affects the human brain and cognition, and emphasize an important role of X-linked genes in intrinsic neural coupling.
    Cerebral Cortex 10/2015; DOI:10.1093/cercor/bhv240 · 8.67 Impact Factor
  • Source
    • "on in ways that help to normalize patterns of connectivity and establish more mature brain networks , again starting as early as possible in infancy . Rapid breakthroughs in neuroscience have emphasized the gradual specialization and refinement of neural networks and cortical hubs as the hallmark of efficient , flexible adult cognition ( e . g . , Buckner et al . , 2009 ) . This implies that clinical endpoints for intervention should not be limited to specialized brain regions or domain - specific systems , but instead must translate to changes at the level of network organization and efficiency . Finally , because cognition evolves across time , we emphasize that it is likely that the most effective t"
    [Show abstract] [Hide abstract]
    ABSTRACT: Much progress has been made toward behavioral and pharmacological intervention in intellectual disability, which was once thought too difficult to treat. Down syndrome (DS) research has shown rapid advances, and clinical trials are currently underway, with more on the horizon. Here, we review the literature on the emergent profile of cognitive development in DS, emphasizing that treatment approaches must consider how some " end state " impairments, such as language deficits, may develop from early alterations in neural systems beginning in infancy. Specifically, we highlight evidence suggesting that there are pre-and early postnatal alterations in brain structure and function in DS, resulting in disturbed network function across development. We stress that these early alterations are likely amplified by Alzheimer's disease (AD) progression and poor sleep. Focusing on three network hubs (prefrontal cortex, hippocampus, and cerebellum), we discuss how these regions may relate to evolving deficits in cognitive function in individuals with DS, and to their language profile in particular.
    Frontiers in Behavioral Neuroscience 10/2015; 9(232):1-15. DOI:10.3389/fnbeh.2015.00232 · 3.27 Impact Factor
  • Source
    • "In particular, a number of DTI studies in AD patients and mild cognitive impairment subjects have reported reduced FA values in multiple regions, however, areas with more consistent findings include the hippocampal formation [39], parahippocampal gyrus [41], and the cingulum bundle [23] [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The apolipoprotein E (APOE) ɛ4 allele is the best established genetic risk factor for Alzheimer's disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A large sample of healthy young adolescents (n = 575) were selected from the European neuroimaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm2 and isotropic resolution of 2.4×2.4×2.4 mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE ɛ4 and ɛ2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life.
    Journal of Alzheimer's disease: JAD 09/2015; 47(4-4):977-984. DOI:10.3233/JAD-140519 · 4.15 Impact Factor
Show more