Pronounced Structural and Functional Damage in Early Adult Pediatric-Onset Multiple Sclerosis with No or Minimal Clinical Disability.
ABSTRACT: Pediatric-onset multiple sclerosis (POMS) may represent a model of vulnerability to damage occurring during a period of active maturation of the human brain. Whereas adaptive mechanisms seem to take place in the POMS brain in the short-medium term, natural history studies have shown that these patients reach irreversible disability, despite slower progression, at a significantly younger age than adult-onset MS (AOMS) patients. We tested for the first time whether significant brain alterations already occurred in POMS patients in their early adulthood and with no or minimal disability (n?=?15) in comparison with age- and disability-matched AOMS patients (n?=?14) and to normal controls (NC, n?=?20). We used a multimodal MRI approach by modeling, using FSL, voxelwise measures of microstructural integrity of white matter tracts and gray matter volumes with those of intra- and internetwork functional connectivity (FC) (analysis of variance, p???0.01, corrected for multiple comparisons across space). POMS patients showed, when compared with both NC and AOMS patients, altered measures of diffusion tensor imaging (reduced fractional anisotropy and/or increased diffusivities) and higher probability of lesion occurrence in a clinically eloquent region for physical disability such as the posterior corona radiata. In addition, POMS patients showed, compared with the other two groups, reduced long-range FC, assessed from resting functional MRI, between default mode network and secondary visual network, whose interaction subserves important cognitive functions such as spatial attention and visual learning. Overall, this pattern of structural damage and brain connectivity disruption in early adult POMS patients with no or minimal clinical disability might explain their unfavorable clinical outcome in the long term.
Project description:<h4>Objective</h4>To determine whether pediatric-onset multiple sclerosis (POMS) and adults-onset multiple sclerosis (AOMS) patients are different in initial disease severity and recovery and to investigate the associations with peripheral blood mononuclear cells (PBMCs) transcriptional profiles.<h4>Methods</h4>Clinical and radiological severity of first and second relapses and 6-month recovery were analyzed in 2153 multiple sclerosis (MS) patients and compared between POMS (onset at 8-18years old) and AOMS (onset at 19-40 years old) patients. PBMCs transcriptomes of 15 POMS and 15 gender-matched AOMS patients were analyzed 6 months after the first relapse and compared to 55 age-matched healthy controls. Differentially Expressed Genes (DEGs) with a false discovery rate ? 10% were evaluated using the Partek software.<h4>Results</h4>POMS had increased Expanded Disability Status Scale (EDSS) score at first and second relapses, higher brain gadolinium-enhancing T1-lesions volume at first relapse, and more complete recovery after both relapses compared to AOMS. POMS patients, who recovered completely from the first relapse, were characterized by 19 DEGs that were mainly related to suppression of antigen presentation. Six upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls. POMS patients, who showed no recovery from the first relapse, were characterized by 28 DEGs that were mainly associated with B-cell activation. Five upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls.<h4>Interpretation</h4>POMS patients may have more severe first and second relapses than AOMS. However, most often, POMS have better recovery that may be attributed to PBMCs age-related transcriptional profiles associated with antigen presentation and B-cell activation.
Project description:This study aimed to investigate the changes in functional connectivity (FC) within each resting-state network (RSN) and between RSNs in subcortical stroke patients who were well recovered in global motor function. Eleven meaningful RSNs were identified via functional magnetic resonance imaging data from 25 subcortical stroke patients and 22 normal controls using independent component analysis. Compared with normal controls, stroke patients exhibited increased intranetwork FC in the sensorimotor (SMN), visual (VN), auditory (AN), dorsal attention (DAN), and default mode (DMN) networks; they also exhibited decreased intranetwork FC in the frontoparietal network (FPN) and anterior DMN. Stroke patients displayed a shift from no FC in controls to negative internetwork FC between the VN and AN as well as between the VN and SMN. Stroke patients also exhibited weakened positive (anterior and posterior DMN; posterior DMN and right FPN) or negative (AN and right FPN; posterior DMN and dorsal SMN) internetwork FC when compared with normal controls. We suggest that subcortical stroke may induce connectivity changes in multiple functional networks, affecting not only the intranetwork FC within RSNs but also the internetwork FC between these RSNs.
Project description:The objective was to assess dynamic functional connectivity (FC) and local/global connectivity in Parkinson's disease (PD) patients with mild cognitive impairment (PD-MCI) and with normal cognition (PD-NC). The sample included 35 PD patients and 26 healthy controls (HC). Cognitive assessment followed an extensive neuropsychological battery. For resting-state functional MRI (rs-fMRI) analysis, independent component analysis (ICA) was performed and components were located in 7 networks: Subcortical (SC), Auditory (AUD), Somatomotor (SM), visual (VI), cognitive-control (CC), default-mode (DMN), and cerebellar (CB). Dynamic FC analysis was performed using the GIFT toolbox. FC differences between groups in each FC state were analysed with the network-based statistic (NBS) approach. Finally, a graph-theoretical analysis for local/global parameters was performed. The whole sample showed 2 dynamic FC states during the rs-fMRI. PD-MCI patients showed decreased mean dwell time in the hypo-connectivity state (<i>p</i> = 0.030) and showed increased number of state transitions (<i>p</i> = 0.007) compared with the HC. In addition, in the hypo-connectivity state, PD-MCI patients showed reduced inter-network FC between the SM-CC, SM-VI, SM-AUD, CC-VI and SC-DMN compared with the HC (<i>p</i> < 0.05-FDR). These FC alterations in PD-MCI were accompanied by graph-topological alterations in nodes located in the SM network (<i>p</i> < 0.001). In contrast, no differences were found between the PD-NC and HC. Findings suggest the presence of dynamic functional brain deteriorations in PD-MCI that are not present in PD-NC, showing the PD-MCI group dynamic FC dysfunctions, reduced FC mostly between SM-CC networks and graph-topological deteriorations in the SM network. A dynamic FC approach could be helpful to understand cognitive deterioration in PD.
Project description:Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. We investigated whether alterations of intranetwork and internetwork functional connectivity with T2DM progression exist, by using resting-state functional MRI. MRI data were analysed from 19 T2DM patients with normal cognition (DMCN) and 19 T2DM patients with cognitive impairment (DMCI), 19 healthy controls (HC). Functional connectivity among 36 previously well-defined brain regions which consisted of 5 resting-state network (RSN) systems [default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL) and sensorimotor network (SMN)] was investigated at 3 levels (integrity, network and connectivity). Impaired intranetwork and internetwork connectivity were found in T2DM, especially in DMCI, on the basis of the three levels of analysis. The bilateral posterior cerebellum, the right insula, the DMN and the CON were mainly involved in these changes. The functional connectivity strength of specific brain architectures in T2DM was found to be associated with haemoglobin A1c (HbA1c), cognitive score and illness duration. These network alterations in intergroup differences, which were associated with brain functional impairment due to T2DM, indicate that network organizations might be potential biomarkers for predicting the clinical progression, evaluating the cognitive impairment, and further understanding the pathophysiology of T2DM.
Project description:Chronic obstructive pulmonary disease (COPD) affects a large population and is closely associated with cognitive impairment. However, the mechanisms of cognitive impairment in COPD patients have not been unraveled. This study investigated the change in patterns of intrinsic functional hubs using a degree centrality (DC) analysis. The connectivity between these abnormal hubs with the remaining brain was also investigated using functional connectivity (FC). Nineteen stable patients with COPD and 20 normal controls(NC) underwent functional magnetic resonance imaging (MRI) examinations and clinical and neuropsychologic assessments. We measured the voxel-wise DC across the whole brain gray matter and the seed-based FC between these abnormal hubs in the remaining brain matter; the group difference was calculated. A partial correlation analysis was performed to assess the relationship between the abnormal DC and clinical variables in COPD patients. Compared to NC, the patients with COPD exhibited significantly decreased DC in the right lingual gyrus (LG), bilateral supplementary motor area (SMA), and right paracentral lobule (PCL). A further seed-based FC analysis found that COPD patients demonstrated significantly decreased FC between these abnormal hubs in several brain areas, including the left cerebellum anterior lobe, left lingual gyrus, left fusiform gyrus, right insula, right inferior frontal gyrus, limbic lobe, cingulate gyrus, left putamen, lentiform nucleus, right precuneus, and right paracentral lobule. A partial correlation analysis showed that the decreased DC in the right PCL was positively correlated with the FEV1 and FEV1/FVC, and the decreased DC in the SMA was positively correlated with naming and pH in COPD patients. This study demonstrates that there are intrinsic functional hubs and connectivity alterations that may reflect the aberrant information communication in the brain of COPD patients. These findings may help provide new insight for understanding the mechanisms of COPD-related cognitive impairment from whole brain functional connections.
Project description:The salience network (SN) serves to identify salient stimuli and to switch between the central executive network (CEN) and the default-mode network (DMN), both of which are impaired in Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI). We hypothesized that both the structural and functional organization of the SN and functional interactions between the SN and CEN/DMN are altered in normal aging and in AD/aMCI. Gray matter volume (GMV) and resting-state functional connectivity (FC) were analyzed from healthy younger (HYC) to older controls (HOC) and from HOC to aMCI and AD patients. All the SN components showed significant differences in the GMV, intranetwork FC, and internetwork FC between the HYC and HOC. Most of the SN components showed differences in the GMV between the HOC and AD and between the aMCI and AD. Compared with the HOC, AD patients exhibited significant differences in intra- and internetwork FCs of the SN, whereas aMCI patients demonstrated differences in internetwork FC of the SN. Most of the GMVs and internetwork FCs of the SN and part of the intranetwork FC of the SN were correlated with cognitive differences in older subjects. Our findings suggested that structural and functional impairments of the SN may occur as early as in normal aging and that functional disconnection between the SN and CEN/ DMN may also be associated with both normal aging and disease progression.
Project description:Emerging research suggests spatial neglect after right stroke is linked to dysfunctional attention and motor networks. Advanced functional connectivity analysis clarified brain network recovery, however we need to know how networks participate in adaptive motor performance. We need to verify network changes associated with validated functional measures and spatial-motor performance in spatial neglect, especially in patients with large brain lesions and significant disability. This study tested whether disability-relevant spatial neglect associates with different patterns of resting state functional connectivity between motor, dorsal and ventral attention networks (MN, DAN and VAN). Right stroke patients had spatial neglect (n?=?8) or not (n?=?10) on the Behavioural Inattention Test-conventional. Spatial neglect patients had weaker intranetwork VAN connectivity, and reduced internetwork connectivity between VAN and left frontal eye field (DAN), and between VAN and the left primary motor area (MN). These network impairments might explain the co-occurrence of attention and motor deficits in spatial neglect, and open a path to assessing functional connectivity in clinical trials of combined spatial retraining and motor rehabilitation after stroke.
Project description:The brain of congenital blind (CB) has experienced a series of structural and functional alterations, either undesirable outcomes such as atrophy of the visual pathway due to sight loss from birth, or compensatory plasticity to interact efficiently with the environment. However, little is known, so far, about alterations in the functional architecture of resting-state networks (RSNs) in CB. This study aimed to investigate intra- and internetwork connectivity differences between CB and sighted controls (SC), using independent component analysis (ICA) on resting state functional MRI data. Compared with SC, CB showed significantly increased network connectivity within the salience network (SN) and the occipital cortex. Moreover, CB exhibited enhanced internetwork connectivity between the SN and the frontoparietal network (FPN) and between the FPN and the occipital cortex; however, they showed decreased internetwork connectivity between the occipital cortex and the sensorimotor network. These findings suggest that CB experience large scale reorganization at the level of the functional network. More importantly, the enhanced intra- and internetwork connectivity of the SN, FPN, and occipital cortex in CB may improve their abilities to identify salient stimuli, to initiate the executive function, and to top-down control of attention, which are critical for the CB to guide appropriate behavior and to better adaption to the environment.
Project description:Multiple sclerosis (MS) presenting in the pediatric years can lead to landmark disability levels younger in life than adult onset MS and so therefore early and effective treatment remains paramount for long-term outcomes. The goals of MS therapeutics in adults have widened to address multiple mechanisms: anti-inflammatory, neuroprotective, and myelin repair, yet the optimal paradigm for MS therapies in the pediatric population is not known. Pediatric onset MS add complexities due to the ongoing development of the central nervous system and the immune system. Clinical trials have led to an increasing number of pharmaceutical therapies for adult onset MS (AOMS), one POMS randomized controlled trial is completed and other trials are ongoing, yet due to the low prevalence of POMS, the dynamic landscape and risk management of the MS disease modifying therapies (DMT) it remains more difficult to complete trials in POMS. There is consensus that controlled clinical trials leading to appropriate and safe therapies for POMS are important for a multitude of reasons that include unique pediatric pharmacokinetics, short and long-term safety, developmental issues, clinical benefits, and regulatory approval. This review will focus on new treatment goals, paradigm, strategies, monitoring, compliance, and products in the long-term treatment of POMS. The discussion will focus on these new concepts and the published data related to DMT use in POMS. This review provides significant insight into new concepts of treatment goals and current approaches to enhance the lives of the POMS patients now and in the future.
Project description:We examined whether interindividual differences in habitual sleep patterns, quantified as the cumulative habitual total sleep time (cTST) over a 2-w period, were reflected in waking measurements of intranetwork and internetwork functional connectivity (FC) between major nodes of three intrinsically connected networks (ICNs): default mode network (DMN), salience network (SN), and central executive network (CEN).Resting state functional magnetic resonance imaging (fMRI) study using seed-based FC analysis combined with 14-d wrist actigraphy, sleep diaries, and subjective questionnaires (N = 33 healthy adults, mean age 34.3, standard deviation ± 11.6 y). Data were statistically analyzed using multiple linear regression. Fourteen consecutive days of wrist actigraphy in participant's home environment and fMRI scanning on day 14 at the Birmingham University Imaging Centre. Seed-based FC analysis on ICNs from resting-state fMRI data and multiple linear regression analysis performed for each ICN seed and target. cTST was used to predict FC (controlling for age).cTST was specific predictor of intranetwork FC when the mesial prefrontal cortex (MPFC) region of the DMN was used as a seed for FC, with a positive correlation between FC and cTST observed. No significant relationship between FC and cTST was seen for any pair of nodes not including the MPFC. Internetwork FC between the DMN (MPFC) and SN (right anterior insula) was also predicted by cTST, with a negative correlation observed between FC and cTST.This study improves understanding of the relationship between intranetwork and internetwork functional connectivity of intrinsically connected networks (ICNs) in relation to habitual sleep quality and duration. The cumulative amount of sleep that participants achieved over a 14-d period was significantly predictive of intranetwork and inter-network functional connectivity of ICNs, an observation that may underlie the link between sleep status and cognitive performance.