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Loss of 'small-world' networks in Alzheimer's disease: graph analysis of FMRI resting-state functional connectivity.

Sanz-Arigita EJ, Schoonheim MM, Damoiseaux JS, Rombouts SA, Maris E, Barkhof F, Scheltens P, Stam CJ - PLoS ONE (2010)

Bottom Line: Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient.This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands. e.sanz.arigita@gmail.com

ABSTRACT

Background: Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.

Methodology/principal findings: 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.

Conclusions/significance: We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

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Related in: MedlinePlus

Effect of increased functional connectivity in secondary atrophy sites.Theoretical interpretation of simultaneous longer atrophy and shorter functional path length in AD. Initial correlated atrophy between vertices (1) is decoupled due to compensatory functional connectivity involving secondary atrophy vertices (2). The appearance of new functional edges (3 - shorter functional L) results in preserved functionality of secondary atrophy vertices (4) and the disappearance of cortical thickness edges linking to the primary atrophy vertex (5 - longer structural L). The rerouted functional flow could still gain partial access to the primary atrophy site and the rest of the network (6).
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pone-0013788-g006: Effect of increased functional connectivity in secondary atrophy sites.Theoretical interpretation of simultaneous longer atrophy and shorter functional path length in AD. Initial correlated atrophy between vertices (1) is decoupled due to compensatory functional connectivity involving secondary atrophy vertices (2). The appearance of new functional edges (3 - shorter functional L) results in preserved functionality of secondary atrophy vertices (4) and the disappearance of cortical thickness edges linking to the primary atrophy vertex (5 - longer structural L). The rerouted functional flow could still gain partial access to the primary atrophy site and the rest of the network (6).

Mentions: The integration of structural and functional networks represents a critical challenge in connectivity research. The elegant study by He et al. [19] on the analysis of cortical thickness intercorrelations exemplifies this difficulty, describing a structural network characterized by a long path length that is in direct contrast with the presently described shorter functional path length. How is it possible to imagine the structure of a network with lower structural connectivity and yet supporting higher functional connectivity? The effect of compensatory activity on secondary atrophy sites can offer a tentative explanation. Localized cortical atrophy might result from secondary axonal and trans-synaptic degeneration following primary injury ([65]; [66] for a review). This in turn can induce changes in metabolism at brain regions far removed from the primary atrophy site [67], some of which are of compensatory nature [14]. We hypothesize that, in Alzheimer's disease, compensatory increases in functional connectivity could help maintain the functionality and structural integrity of secondary atrophy sites, with two main consequences at network level: 1) relative increases of cortical thickness path length, and 2) relative decreases of functional path length (Figure 6). Additionally, the rerouted functional flow could still gain partial access to the rest of the network.


Loss of 'small-world' networks in Alzheimer's disease: graph analysis of FMRI resting-state functional connectivity.

Sanz-Arigita EJ, Schoonheim MM, Damoiseaux JS, Rombouts SA, Maris E, Barkhof F, Scheltens P, Stam CJ - PLoS ONE (2010)

Effect of increased functional connectivity in secondary atrophy sites.Theoretical interpretation of simultaneous longer atrophy and shorter functional path length in AD. Initial correlated atrophy between vertices (1) is decoupled due to compensatory functional connectivity involving secondary atrophy vertices (2). The appearance of new functional edges (3 - shorter functional L) results in preserved functionality of secondary atrophy vertices (4) and the disappearance of cortical thickness edges linking to the primary atrophy vertex (5 - longer structural L). The rerouted functional flow could still gain partial access to the primary atrophy site and the rest of the network (6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967467&req=5

pone-0013788-g006: Effect of increased functional connectivity in secondary atrophy sites.Theoretical interpretation of simultaneous longer atrophy and shorter functional path length in AD. Initial correlated atrophy between vertices (1) is decoupled due to compensatory functional connectivity involving secondary atrophy vertices (2). The appearance of new functional edges (3 - shorter functional L) results in preserved functionality of secondary atrophy vertices (4) and the disappearance of cortical thickness edges linking to the primary atrophy vertex (5 - longer structural L). The rerouted functional flow could still gain partial access to the primary atrophy site and the rest of the network (6).
Mentions: The integration of structural and functional networks represents a critical challenge in connectivity research. The elegant study by He et al. [19] on the analysis of cortical thickness intercorrelations exemplifies this difficulty, describing a structural network characterized by a long path length that is in direct contrast with the presently described shorter functional path length. How is it possible to imagine the structure of a network with lower structural connectivity and yet supporting higher functional connectivity? The effect of compensatory activity on secondary atrophy sites can offer a tentative explanation. Localized cortical atrophy might result from secondary axonal and trans-synaptic degeneration following primary injury ([65]; [66] for a review). This in turn can induce changes in metabolism at brain regions far removed from the primary atrophy site [67], some of which are of compensatory nature [14]. We hypothesize that, in Alzheimer's disease, compensatory increases in functional connectivity could help maintain the functionality and structural integrity of secondary atrophy sites, with two main consequences at network level: 1) relative increases of cortical thickness path length, and 2) relative decreases of functional path length (Figure 6). Additionally, the rerouted functional flow could still gain partial access to the rest of the network.

Bottom Line: Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient.This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands. e.sanz.arigita@gmail.com

ABSTRACT

Background: Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.

Methodology/principal findings: 18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.

Conclusions/significance: We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.

Show MeSH
Related in: MedlinePlus