Altered topological properties of the cortical motor‐related network in patients with subcortical stroke revealed by graph theoretical analysis

Cerebral neuroplasticity after stroke has been elucidated by functional neuroimaging. However, little is known concerning how topological properties of the cortical motor‐related network evolved following subcortical stroke. In the present study, we investigated 24 subcortical stroke patients with only left motor pathway damaged and 24 matched healthy controls. A cortical motor‐related network consisting of 20 brain regions remote from the primary lesion was constructed using resting‐state functional MRI datasets. We subsequently used graph theoretical approaches to analyze the topological properties of this network in both stroke patients and healthy controls. In addition, we divided the stroke patients into two subgroups according to their outcomes in hand function to explore relationships between topological properties of this network and outcomes in hand function. Although we observed that the cortical motor‐related network in both healthy controls and stroke patients exhibited small‐world topology, the local efficiency of this network in stroke patients is higher than and global efficiency is lower than those in healthy controls. In addition, striking alterations in the betweenness centrality of regions were found in stroke patients, including the contralesional supplementary motor area, dorsolateral premotor cortex, and anterior inferior cerebellum. Moreover, we observed significant correlations between betweenness centrality of regions and Fugl‐Meyer assessment scores. A tendency for the cortical motor‐related network to be close to a regular configuration and altered betweenness centrality of regions were demonstrated in patients with subcortical stroke. This study provided insight into functional organization after subcortical stroke from the viewpoint of network topology. Hum Brain Mapp 35:3343–3359, 2014. © 2013 Wiley Periodicals, Inc .     

Abnormal functional connectivity and cortical integrity influence dominant hand motor disability in multiple sclerosis: a multimodal analysis

Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting‐state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting‐state fMRI, T1‐weighted and T2‐weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease‐related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor preserved MS participants had stronger FC in structurally intact visual information processing regions relative to motor impaired MS participants. Motor impaired MS participants showed weaker FC in the sensorimotor and somatosensory association cortices and more severe structural damage throughout the brain compared with the other groups. Logistic regression analysis showed that regional MTR predicted motor disability beyond the impact of global atrophy whereas regional grey matter volume did not. More importantly, as the first multimodal analysis combining resting‐state fMRI, T1‐weighted, T2‐weighted and MTR images in MS, we demonstrate how a combination of structural and functional changes may contribute to motor impairment or preservation in MS. Hum Brain Mapp 37:4262–4275, 2016. © 2016 Wiley Periodicals, Inc.     

Functional connectivity in amygdalar‐sensory/(pre)motor networks at rest: new evidence from the Human Connectome Project

The word ‘e‐motion’ derives from the Latin word ‘ex‐moveo’ which literally means ‘moving away from something/somebody’. Emotions are thus fundamental to prime action and goal‐directed behavior with obvious implications for individual's survival. However, the brain mechanisms underlying the interactions between emotional and motor cortical systems remain poorly understood. A recent diffusion tensor imaging study in humans has reported the existence of direct anatomical connections between the amygdala and sensory/(pre)motor cortices, corroborating an initial observation in animal research. Nevertheless, the functional significance of these amygdala‐sensory/(pre)motor pathways remain uncertain. More specifically, it is currently unclear whether a distinct amygdala‐sensory/(pre)motor circuit can be identified with resting‐state functional magnetic resonance imaging (rs‐fMRI). This is a key issue, as rs‐fMRI offers an opportunity to simultaneously examine distinct neural circuits that underpin different cognitive, emotional and motor functions, while minimizing task‐related performance confounds. We therefore tested the hypothesis that the amygdala and sensory/(pre)motor cortices could be identified as part of the same resting‐state functional connectivity network. To this end, we examined independent component analysis results in a very large rs‐fMRI data‐set drawn from the Human Connectome Project (n = 820 participants, mean age: 28.5 years). To our knowledge, we report for the first time the existence of a distinct amygdala‐sensory/(pre)motor functional network at rest. rs‐fMRI studies are now warranted to examine potential abnormalities in this circuit in psychiatric and neurological diseases that may be associated with alterations in the amygdala‐sensory/(pre)motor pathways (e.g. conversion disorders, impulse control disorders, amyotrophic lateral sclerosis and multiple sclerosis).     

Analysis of structure–function network decoupling in the brain systems of spastic diplegic cerebral palsy

Manifestation of the functionalities from the structural brain network is becoming increasingly important to understand a brain disease. With the aim of investigating the differential structure–function couplings according to network systems, we investigated the structural and functional brain networks of patients with spastic diplegic cerebral palsy with periventricular leukomalacia compared to healthy controls. The structural and functional networks of the whole brain and motor system, constructed using deterministic and probabilistic tractography of diffusion tensor magnetic resonance images and Pearson and partial correlation analyses of resting‐state functional magnetic resonance images, showed differential embedding of functional networks in the structural networks in patients. In the whole‐brain network of patients, significantly reduced global network efficiency compared to healthy controls were found in the structural networks but not in the functional networks, resulting in reduced structural–functional coupling. On the contrary, the motor network of patients had a significantly lower functional network efficiency over the intact structural network and a lower structure–function coupling than the control group. This reduced coupling but reverse directionality in the whole‐brain and motor networks of patients was prominent particularly between the probabilistic structural and partial correlation‐based functional networks. Intact (or less deficient) functional network over impaired structural networks of the whole brain and highly impaired functional network topology over the intact structural motor network might subserve relatively preserved cognitions and impaired motor functions in cerebral palsy. This study suggests that the structure–function relationship, evaluated specifically using sparse functional connectivity, may reveal important clues to functional reorganization in cerebral palsy. Hum Brain Mapp 38:5292–5306, 2017. © 2017 Wiley Periodicals, Inc.     

Do premorbid impairments predict emergent ‘prodromal’ symptoms in young relatives at risk for schizophrenia?

Aims: Individuals at risk for developing schizophrenia (SZ) in the future frequently exhibit subtle behavioural and neurobiological abnormalities in their childhood. A better understanding of the role of these abnormalities in predicting later onset of ‘prodromal’ symptoms or psychosis may help in early identification of SZ. Methods: In an ongoing prospective follow‐up study of young genetically at‐risk relatives of patients with SZ, we studied the prevalence of problems in premorbid social adjustment and childhood psychopathology and examined their relationship with the presence and progression of ‘prodromal’ symptoms of SZ. Results: Growth curve analyses showed that ‘prodromal’ symptoms, as measured by the Scale of ‘Prodromal’ Symptoms, increased during follow‐up. Premorbid maladjustment and childhood behavioural disturbances were cross‐sectionally correlated broadly with ‘prodromal’ symptomatology scores. Longitudinal analyses revealed that behavioural disturbances, but not childhood maladjustment at baseline, significantly predicted increases in ‘prodromal’ symptomatology during the 2‐year study period. Conclusion: Premorbid behavioural disturbance and maladjustment may predict the later emergence of ‘prodromal’ symptoms. ‘Prodromal’ symptoms in young at‐risk relatives may define a subgroup worthy of follow‐up into the age of risk for psychosis in order to cost‐effectively characterize the predictors of psychotic symptoms and SZ.     

Functional connectivity changes in multiple sclerosis patients: A graph analytical study of MEG resting state data

Multiple sclerosis (MS) is characterized by extensive damage in the central nervous system. Within this field, there is a strong need for more advanced, functional imaging measures, as abnormalities measured with structural imaging insufficiently explain clinicocognitive decline in MS. In this study we investigated functional connectivity changes in MS using resting‐state magnetoencephalography (MEG). Data from 34 MS patients and 28 age and gender‐matched controls was assessed using synchronization likelihood (SL) as a measure of functional interaction strength between brain regions, and graph analysis to characterize topological patterns of connectivity changes. Cognition was assessed using extensive neuropsychological evaluation. Structural measures included brain and lesion volumes, using MRI. Results show SL increases in MS patients in theta, lower alpha and beta bands, with decreases in the upper alpha band. Graph analysis revealed a more regular topology in the lower alpha band in patients, indicated by an increased path length (λ) and clustering coefficient (γ). Attention and working memory domains were impaired, with decreased brain volumes. A stepwise linear regression model using clinical, MRI and MEG parameters as predictors revealed that only increases in lower alpha band γ predicted impaired cognition. Cognitive impairments and related altered connectivity patterns were found to be especially predominant in male patients. These results show specific functional changes in MS as measured with MEG. Only changes in network topology were related to poorer cognitive outcome. This indicates the value of graph analysis beyond traditional structural and functional measures, with possible implications for diagnostic and/or prognostic purposes in MS. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing‐remitting multiple sclerosis

Background: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast “connectometry” approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS . Methods: We used diffusion spectrum and resting‐state functional MRI (rs‐fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing‐remitting MS patients and 16 healthy controls (HC). We performed multicontrast “connectometry” by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy‐GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. Results: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs‐fMRI abnormalities were observed at this early stage. Conclusion: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609–1619, 2015. © 2014 Wiley Periodicals, Inc.     

Abnormal connectivity of the sensorimotor network in patients with MS: A multicenter fMRI study

In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age‐matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI‐measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long‐distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Functional and structural brain networks in epilepsy: What have we learned?

Brain functioning is increasingly seen as a complex interplay of dynamic neural systems that rely on the integrity of structural and functional networks. Recent studies that have investigated functional and structural networks in epilepsy have revealed specific disruptions in connectivity and network topology and, consequently, have led to a shift from “focus” to “networks” in modern epilepsy research. Disruptions in these networks may be associated with cognitive and behavioral impairments often seen in patients with chronic epilepsy. In this review, we aim to provide an overview that would introduce the clinical neurologist and epileptologist to this new theoretical paradigm. We focus on the application of a theory, called “network analysis,” to characterize resting‐state functional and structural networks and discuss current and future clinical applications of network analysis in patients with epilepsy.     

Schizophrenia‐like topological changes in the structural connectome of individuals with subclinical psychotic experiences

Schizophrenia is often regarded as a “dysconnectivity” disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population‐based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion‐weighted MRI. Whole‐brain structural connectomes were derived and a range of global and local GT‐metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair‐wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair‐wise connections illustrates that, at less severe stages of psychosis, white‐matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness. Hum Brain Mapp 36:2629–2643, 2015.© 2015 TheAuthors Human Brain Mapping Published by Wiley Periodicals, Inc .     

Inter‐subject synchronization of brain responses during natural music listening

Music is a cultural universal and a rich part of the human experience. However, little is known about common brain systems that support the processing and integration of extended, naturalistic ‘real‐world’ music stimuli. We examined this question by presenting extended excerpts of symphonic music, and two pseudomusical stimuli in which the temporal and spectral structure of the Natural Music condition were disrupted, to non‐musician participants undergoing functional brain imaging and analysing synchronized spatiotemporal activity patterns between listeners. We found that music synchronizes brain responses across listeners in bilateral auditory midbrain and thalamus, primary auditory and auditory association cortex, right‐lateralized structures in frontal and parietal cortex, and motor planning regions of the brain. These effects were greater for natural music compared to the pseudo‐musical control conditions. Remarkably, inter‐subject synchronization in the inferior colliculus and medial geniculate nucleus was also greater for the natural music condition, indicating that synchronization at these early stages of auditory processing is not simply driven by spectro‐temporal features of the stimulus. Increased synchronization during music listening was also evident in a right‐hemisphere fronto‐parietal attention network and bilateral cortical regions involved in motor planning. While these brain structures have previously been implicated in various aspects of musical processing, our results are the first to show that these regions track structural elements of a musical stimulus over extended time periods lasting minutes. Our results show that a hierarchical distributed network is synchronized between individuals during the processing of extended musical sequences, and provide new insight into the temporal integration of complex and biologically salient auditory sequences.     

Meta‐analytic evidence for altered mesolimbic responses to reward in schizophrenia

Dysfunction of reward‐related neural circuitry in schizophrenia (SCZ) has been widely reported, and may provide insight into the motivational and cognitive disturbances that characterize the disorder. Although previous meta‐analyses of reward learning paradigms in SCZ have been performed, a meta‐analysis of whole‐brain coordinate maps in SCZ alone has not been conducted. In this study, we performed an activation likelihood estimate (ALE) meta‐analysis, and performed a follow‐up analysis of functional connectivity and functional decoding of identified regions. We report several salient findings that extend prior work in this area. First, an alteration in reward‐related activation was observed in the right ventral striatum, but this was not solely driven by hypoactivation in the SCZ group compared to healthy controls. Second, the region was characterized by functional connectivity primarily with the lateral prefrontal cortex and pre‐supplementary motor area (preSMA), as well as subcortical regions such as the thalamus which show structural deficits in SCZ. Finally, although the meta‐analysis showed no regions outside the ventral striatum to be significantly altered, regions with higher functional connectivity with the ventral striatum showed a greater number of subthreshold foci. Together, these findings confirm the alteration of ventral striatal function in SCZ, but suggest that a network‐based approach may assist future analysis of the functional underpinnings of the disorder.     

Investigating the role of the corpus callosum in regulating motor overflow in multiple sclerosis

The corpus callosum (CC) is commonly affected in multiple sclerosis (MS), however, sensitive behavioral measures of MS-related CC pathology are lacking. The CC is considered a key structure in the mediation of a type of involuntary movement known as motor overflow. In this study, we sought to characterize the impact of CC damage on motor overflow in MS. Twenty MS participants and 20 controls performed a unilateral force production task. Motor overflow (involuntary force) in the non-active hand was measured while the active hand performed the task. CC volume and lesion load were calculated for MS participants using T2-weighted MRI. We found no group differences in motor overflow; however, motor overflow correlated significantly with MS disease severity [Expanded disability status scale (EDSS)]. CC damage (lesions and decreased volume) did not correlate with motor overflow. This study suggests that CC damage may not directly lead to changes in the regulation of motor overflow. Rather, findings support the notion that a wider network of structures may mediate the production and suppression of motor overflow.     

Evaluating the organizational structure and specificity of network topology within the face processing system

There is increasing appreciation that network‐level interactions among regions produce components of face processing previously ascribed to individual regions. Our goals were to use an exhaustive data‐driven approach to derive and quantify the topology of directed functional connections within a priori defined nodes of the face processing network and evaluate whether the topology is category‐specific. Young adults were scanned with fMRI as they viewed movies of faces, objects, and scenes. We employed GIMME to model effective connectivity among core and extended face processing regions, which allowed us to evaluate all possible directional connections, under each viewing condition (face, object, place). During face processing, we observed directional connections from the right posterior superior temporal sulcus to both the right occipital face area and right fusiform face area (FFA), which does not reflect the topology reported in prior studies. We observed connectivity between core and extended regions during face processing, but this limited to a feed‐forward connection from the FFA to the amygdala. Finally, the topology of connections was unique to face processing. These findings suggest that the pattern of directed functional connections within the face processing network, particularly in the right core regions, may not be as hierarchical and feed‐forward as described previously. Our findings support the notion that topologies of network connections are specialized, emergent, and dynamically responsive to task demands.     

Mapping the structural and functional network architecture of the medial temporal lobe using 7T MRI

Medial temporal lobe (MTL) subregions play integral roles in memory function and are differentially affected in various neurological and psychiatric disorders. The ability to structurally and functionally characterize these subregions may be important to understanding MTL physiology and diagnosing diseases involving the MTL. In this study, we characterized network architecture of the MTL in healthy subjects (n = 31) using both resting state functional MRI and MTL‐focused T2‐weighted structural MRI at 7 tesla. Ten MTL subregions per hemisphere, including hippocampal subfields and cortical regions of the parahippocampal gyrus, were segmented for each subject using a multi‐atlas algorithm. Both structural covariance matrices from correlations of subregion volumes across subjects, and functional connectivity matrices from correlations between subregion BOLD time series were generated. We found a moderate structural and strong functional inter‐hemispheric symmetry. Several bilateral hippocampal subregions (CA1, dentate gyrus, and subiculum) emerged as functional network hubs. We also observed that the structural and functional networks naturally separated into two modules closely corresponding to (a) bilateral hippocampal formations, and (b) bilateral extra‐hippocampal structures. Finally, we found a significant correlation in structural and functional connectivity (r = 0.25). Our findings represent a comprehensive analysis of network topology of the MTL at the subregion level. We share our data, methods, and findings as a reference for imaging methods and disease‐based research.     

Measuring risk‐taking in mice: balancing the risk between seeking reward and danger

Assessing risk is an essential part of human behaviour and may be disrupted in a number of psychiatric conditions. Currently, in many animal experimental designs the basis of the potential ‘risk’ is loss or attenuation of reward, which fail to capture ‘real‐life’ risky situations where there is a trade‐off between a separate cost and reward. The development of rodent tasks where two separate and conflicting factors are traded against each other has begun to address this discrepancy. Here, we discuss the merits of these risk‐taking tasks and describe the development of a novel test for mice – the ‘predator‐odour risk‐taking’ task. This paradigm encapsulates a naturalistic approach to measuring risk‐taking behaviour where mice have to balance the benefit of gaining a food reward with the cost of exposure to a predator odour using a range of different odours (rat, cat and fox). We show that the ‘predator‐odour risk‐taking’ task was sensitive to the trade‐off between cost and benefit by demonstrating reduced motivation to collect food reward in the presence of these different predator odours in two strains of mice and, also, if the value of the food reward was reduced. The ‘predator‐odour risk‐taking’ task therefore provides a strong platform for the investigation of the genetic substrates of risk‐taking behaviour using mouse models, and adds a further dimension to other recently developed rodent tests.     

Brain dynamics of post‐task resting state are influenced by expertise: Insights from baseball players

Post‐task resting state dynamics can be viewed as a task‐driven state where behavioral performance is improved through endogenous, non‐explicit learning. Tasks that have intrinsic value for individuals are hypothesized to produce post‐task resting state dynamics that promote learning. We measured simultaneous fMRI/EEG and DTI in Division‐1 collegiate baseball players and compared to a group of controls, examining differences in both functional and structural connectivity. Participants performed a surrogate baseball pitch Go/No‐Go task before a resting state scan, and we compared post‐task resting state connectivity using a seed‐based analysis from the supplementary motor area (SMA), an area whose activity discriminated players and controls in our previous results using this task. Although both groups were equally trained on the task, the experts showed differential activity in their post‐task resting state consistent with motor learning. Specifically, we found (1) differences in bilateral SMA–L Insula functional connectivity between experts and controls that may reflect group differences in motor learning, (2) differences in BOLD‐alpha oscillation correlations between groups suggests variability in modulatory attention in the post‐task state, and (3) group differences between BOLD‐beta oscillations that may indicate cognitive processing of motor inhibition. Structural connectivity analysis identified group differences in portions of the functionally derived network, suggesting that functional differences may also partially arise from variability in the underlying white matter pathways. Generally, we find that brain dynamics in the post‐task resting state differ as a function of subject expertise and potentially result from differences in both functional and structural connectivity. Hum Brain Mapp 37:4454–4471, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Thalamocortical sensorimotor circuit in multiple sclerosis: An integrated structural and electrophysiological assessment

Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing‐Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high‐resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1–M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Intranetwork and internetwork functional connectivity abnormalities in pediatric multiple sclerosis

Active motor functional magnetic resonance imaging (fMRI) studies have shown that pediatric multiple sclerosis (MS) patients have a strictly lateralized pattern of activations and a preserved functional connectivity (FC) within the motor system when compared to age‐matched healthy controls. However, it is still not clear whether a preserved FC in pediatric MS is present only in the motor system, or involves other relevant functional system. Resting‐state (RS) fMRI is a valuable tool for an unbiased investigation of FC abnormalities of multiple networks. This study explored abnormalities of RS FC within and between large‐scale neuronal networks from 44 pediatric MS patients and 27 controls and their correlation with clinical, neuropsychological, and conventional MRI measures. Compared to controls, pediatric MS patients had a decreased FC of several regions of the sensorimotor, secondary visual, default‐mode (DMN), executive control, and bilateral working memory (WMN) networks. They also experienced an increased FC in the right medial frontal gyrus of the attention network, which was correlated with T2 lesion volume. Cognitively impaired patients had decreased RS FC of the right precuneus of the left WMN. An increased FC between the sensorimotor network and the DMN, and between the L WMN and the attention network as well as a decreased FC between L WMN and the DMN were also found. A distributed pattern of FC abnormalities within large‐scale neuronal networks occurs in pediatric MS patients, contributes to their cognitive status, and is partially driven by focal white matter lesions. Internetwork connectivity is relatively preserved in these patients. Hum Brain Mapp 35:4180–4192, 2014. © 2014 Wiley Periodicals, Inc .