Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis

Abstract

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.resting state | BOLD fMRI | diffusion tensor imaging | fractional anisotropy | neurological U nderstanding how disease processes affect functional interactions in the CNS is a core challenge of neuroscience research. fMRI connectivity has become an important tool for revealing large-scale network interactions by analyzing correlations in intrinsic fluctuations of the BOLD signal (1). This method is sensitive to plastic as well as developmental changes of the functional architecture (2-5), and has successfully linked specific cognitive syndromes to the pathology of distinct functional systems (e.g., spatial neglect after stroke, different forms of dementias, and healthy aging) (6-8). The structural wiring of the brain plays an essential role in shaping the spatial patterns of functional interactions (9, 10). However, the activity correlations are not fully determined by the anatomical connections and, thus, provide complementary information about network organization (11). Especially in the context of neurological damage, the functional covariance structure may document pathological effects well beyond focal damage, indicating the complex changes of interactions that occur in distributed networks (12)(13)(14). Commonly, the coupling strength of spontaneous brain activity is thought to be a direct proxy for the functioning of brain networks, with stronger interactions also reflecting a stronger computational capacity (15,16).In this study we have investigated how cognitive pathology due to neurological damage in multiple sclerosis (MS) is reflected in changes of structural and functional connectivity. Compared with other CNS pathologies, MS stands out due to the prominent involvement of the central white matter. During the disease process, the immune system exerts inflammatory insults to neurona...

Principal components of functional connectivity: A new approach to study dynamic brain connectivity during rest

“…However, we also confirmed the bilateral parahippocampal gyri, right amygdala, left thalamus and left midtemporal pole as more strongly connected in RRMS patients (Richiardi et al, 2012). Such selective increased FC has been reported by several other studies as well (Bonavita et al, 2011;Dogonowski et al, 2013;Hawellek et al, 2011;Richiardi et al, 2012;Rocca et al, 2012;Roosendaal et al, 2010) and has been interpreted as a compensatory mechanism (Bonavita et al, 2011;Roosendaal et al, 2010) because activation studies have shown increased activity in regions devoted to the task and the recruitment of additional regions in MS patients (Pantano et al, 2002;Rocca et al, 2005). It is however also possible that these increases originate from a loss of flexibility in functional interactions, rather than as a compensatory mechanism (Hawellek et al, 2011).…”

“…The importance of these regions suggests that the dynamic FC of at least part of the DMN is altered in patients. These results add to, and complement, several studies which have reported disturbed stationary FC in different parts of the DMN in MS patients (Bonavita et al, 2011;Hawellek et al, 2011;Richiardi et al, 2012;Rocca et al, 2012). The distinction between posterior and anterior/temporal DMN regions seen in eigenconnectivity 6 is similar to the DMN fragmentation observed in Allen et al (in press) and would be missed in conventional stationary FC analyses.…”

“…Alternative imaging methods, such as resting-state fMRI, have started to address the issue of hidden damage and shown disrupted stationary FC. While some studies restricted their analysis to the DMN or motor regions (Bonavita et al, 2011;Dogonowski et al, 2013;Lowe et al, 2002;Rocca et al, 2010), others have reported changes in several large-scale resting state networks, including the sensorimotor and executive control networks (Hawellek et al, 2011;Richiardi et al, 2012;Rocca et al, 2012;Roosendaal et al, 2010). Together, these results are very promising for characterizing the functional pathology of MS, but the relationship between structural damage and functional changes is still poorly understood (Schoonheim and Filippi, 2012).…”

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity

“…Along with the decreased connectivities, these might reflect functional reorganisation to cope with pathological damage, in keeping with results from several imaging studies in MS (Reddy et al, 2000a;Morgen et al, 2004;Mainero et al, 2004;Morgen et al, 2007;Trapp et al, 1998;Hawellek et al, 2011). Compensatory activation is often considered as a process arising at early stages, which tends to be lost with disease progression (Bonavita et al, 2011;Roosendaal et al, 2010).…”

“…Given its complementarity with other diagnostic modalities, future studies should further investigate the sensitivity of this approach for patients with suspected MS or clinically isolated syndromes, and explore its use for monitoring evolution or treatment effects. A particular interest will be the investigation of the link between connectivity alterations and clinically-relevant scales, as interesting links with cognitive performance have been found by other authors (Hawellek et al, 2011). Additionally, spatial relationship between lesion locations and connectivity alterations at the single subject level would be of great interest in order to improve result interpretation with respect to specific attack types.…”