ReviewWorking memory performance of early MS patients correlates inversely with modularity increases in resting state functional connectivity networks
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS). Its pathology is characterized by regional demyelination and axonal damage appearing as focal lesions. This leads to disruptions in connectivity patterns of subcortical areas, dysfunction of spinal cord pathways, as well as changes in cortico-cortical connections, which can translate to motor, sensory and/or cognitive dysfunction. However, these behavioral abnormalities are not always perceptible with conventional clinical examination. There is evidence that at early stages of the disease, functional adaptive changes occur as a means to limit clinical manifestations of tissue damage (Audoin et al., 2005, Mainero et al., 2004, Pantano et al., 2002a, Pantano et al., 2002b). Due to the scattered nature of the structural abnormalities, the relationship between lesions and clinical disability is not straightforward.
Aiming to reach a better understanding of the disease to facilitate diagnosis and treatment, preferably at very early stages, considerable research efforts are currently being devoted to neuroimaging methods, at both structural and functional levels (Bonzano et al., 2009, Rossi et al., 2012). Functional neuroimaging studies in MS have shown the potential of providing information about functional adaptive changes and their relation with cognitive performance (Audoin et al., 2005, Bonavita et al., 2011, Bonzano et al., 2009).
This field of research has recently benefited from the observation that the human brain at the large-scale level behaves as a complex network of functionally interacting elements (Bullmore and Sporns, 2009, Rubinov and Sporns, 2010, Sporns et al., 2004). This network can be modeled using tools such as graph theory, which—in combination with neuroimaging techniques—allow going beyond the mapping of local activity changes and studying the re-organization of structural and functional connectivity (Zhou et al., 2006)—for a review see Guye et al. (2010). Graph theoretical approaches have contributed to elucidate patterns of functional connectivity in different brain states (task-related or resting-state) and have shown to be a promising instrument to characterize pathological conditions (Guye et al., 2010). Since connectivity changes associated with brain pathology seem to be highly correlated with cognitive impairment (Audoin et al., 2005, Bonavita et al., 2011, Guye et al., 2008, He et al., 2007, Tecchio et al., 2008), it has been speculated that a quantification of the abnormalities in topology (Rossi et al., 2012) and efficiency (Cover et al., 2006) of brain networks could be a good indicator of disease progression.
An important property of functional connectivity networks is their non-trivial modular structure. Network modularity is a topological property that provides information about the degree of decomposability of a network, by identifying modules of densely interconnected nodes, which are sparsely connected with nodes in other modules (Newman, 2006, Newman and Girvan, 2004). Several studies have reported an overlap between modular organization in the anatomical brain network and its functional specializations (Chen et al., 2008, Ferrarini et al., 2009, Meunier et al., 2009b, Wu et al., 2011b). Furthermore, changes in the modular structure of functional networks have been observed in the healthy brain related to normal aging (Chen et al., 2011, Meunier et al., 2009a, Wu et al., 2011a), learning processes (Bassett et al., 2011), sleep (Tagliazucchi et al., 2012), and in diverse pathological conditions such as chronic back pain (Balenzuela et al., 2010), Alzheimer's disease (de Haan et al., 2012, He et al., 2008, Sanz-Arigita et al., 2010), schizophrenia (Alexander-Bloch et al., 2010, Bassett et al., 2008) and epilepsy (Vaessen et al., 2012).
In this study we investigated the network modularity and the ensuing modular structure of functional connectivity networks derived from resting-state fMRI data of early MS patients and matched healthy controls (HC). Here and throughout the manuscript the term “early” refers to patients with minimal or bare of any clinical disability in established clinical measures (such as the EDSS) rather than disease duration. We hypothesized that, as a consequence of the structural abnormalities present in the brain of MS patients, communication between brain modules will be impaired and therefore connectivity will be re-arranged to favor network segregation, resulting in increased modularity when compared to healthy controls. Additional to these analyses, we performed the Paced Auditory Serial Addition Task (PASAT) in a dual task fashion to assess deficiencies in cognitive function, namely working memory, attention and speed of information processing. Even though the group of early MS patients taking part in the study was cognitively normal, our aim when introducing the high cognitive load in the dual task was to limit the brain network resources available during memory performance to compensate for subliminal dysfunction. The correlations between lesion load volume, modularity and behavioral data were then computed in order to test interactions between structure and function.
Section snippets
Subjects
A total of 16 patients in the initial phase of MS [CIS or RRMS according to the revised McDonald criteria (Polman et al., 2011), EDSS ≤ 2.5, T2-lesion volume < 15 mL] (11 females, mean age = 35.3, SD = 8.3, see Table 1) and 20 healthy volunteers (10 females, mean age = 29.9, SD = 7.0) participated in this study. All participants were assessed in sessions 1 and 2, however only 15 healthy controls (9 females, mean age = 31.1, SD = 7.1 years) and 15 patients (10 females, mean age = 35.0, SD = 8.5 years) joined session
Results
The results of the neuropsychological tests are summarized in Table 2.
Discussion
In the present study we show increased modularity values over a wide range of link densities (δ) in large-scale brain networks of the MS group. A decreased accuracy in the dual task performance and a negative correlation between modularity and dual task accuracy were found in the MS group.
In the present study we report increased network modularity values for the MS group. It is known that localized brain lesions can impair global metrics of network topology such as modularity (Gratton et al.,
Funding
This work was supported by the Hessisches Ministerium für Wissenschaft und Kultur—LOEWE Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF).
Acknowledgments
This work was supported by the Hessisches Ministerium für Wissenschaft und Kultur—LOEWE Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF).
We thank Christoph Mayer for patient recruitment, Marion Behrens for methodological advice and valuable discussions, Ulrike Nöth, Ralf Deichmann, Steffen Volz, Astrid Morzelewski and Julia Heiken for extensive MRI support, Julia Dieter for helping with patient recruitment and providing PASAT training to the participants and all subjects for their
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Authors contributed equally to this work.