Resting state networks change in clinically isolated syndrome

Abstract

Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain 'at rest' may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (clinically isolated syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with clinically isolated syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with clinically isolated syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the clinically isolated syndrome group. Thus, early synchronization changes are found in patients with clinically isolated syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis.

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 identified brain regions are largely consistent with those in a previous study by our group, which aimed at discriminating between HC subjects and RRMS patients based on stationary FC (Richiardi et al, 2012); i.e., the left Heschl's gyrus, right rolandic operculum, and right superior parietal gyrus, were identified as being more strongly connected in HC subjects in both studies. Reduced stationary FC in MS patients is indeed commonly observed and is thought to stem from structural damage (Bonavita et al, 2011;Lowe et al, 2002;Richiardi et al, 2012;Roosendaal et al, 2010). 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).…”

“…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

“…Studies have highlighted alterations to the DMN (Buckner et al, 2008) associated with multiple sclerosis (Roosendaal et al, 2010;Bonavita et al, 2011). To investigate this effect more specifically in our data, a subnetwork of the whole-brain graph comprising regions that are part of the DMN was defined (based on the work of Buckner et al (2008), and including the ventral and medial prefrontal cortex, the posterior cingulate and retrosplenial cortex, inferior parietal lobule, lateral temporal cortex, and hippocampal formation.…”

“…Weaker DMN connectivity in the ACC of MS patients was also reported by Bonavita et al (2011) using independent component analysis of fMRI resting-state data. Roosendaal et al (2010) investigated fMRI restingstate networks in patients with clinically isolated syndrome (CIS) and patients with RRMS and observed an increased synchronisation of some resting-state networks in CIS patients which disappeared in those with RRMS, suggesting initial functional compensation that is lost with disease progression. Using ICA and seed correlation, Jones et al (2011) showed significant differences in connectivity at rest between a single MS patient with an important thalamic lesion and a group of controls, in particular in the default mode network.…”