Early structural hub disruption leads to premature functional adaption in multiple sclerosis.

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Combination of structural and functional brain connectivity methods provides a more complete and effective avenue into the investigation of cortical network responses to traumatic brain injury (TBI) and subtle alterations in brain connectivity associated with TBI. Structural connectivity (SC) can be measured using diffusion tensor imaging to evaluate white matter integrity, whereas functional connectivity (FC) can be studied by examining functional correlations within or between functional networks. In this study, the alterations of SC and FC were assessed for TBI patients, with and without chronic symptoms (TBIcs/TBIncs), compared with a healthy control group (CG). The correlation between global SC and FC was significantly increased for both TBI groups compared with CG. SC was significantly lower in the TBIcs group compared with CG, and FC changes were seen in the TBIncs group compared with CG. When comparing TBI groups, FC differences were observed in the TBIcs group compared with the TBIncs group. These observations show that the presence of chronic symptoms is associated with a distinct pattern of SC and FC changes including the atrophy of the SC and a mixture of functional hypoconnectivity and hyperconnectivity, as well as loss of segregation of functional networks.

Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability.

Background: Despite accumulated evidence for adult brain plasticity, the temporal relationships between large-scale functional and structural connectivity changes in human brain networks remain unclear. Methods: By analysing a unique richly detailed 19-week longitudinal neuroimaging dataset, we tested whether macroscopic functional connectivity changes lead to the corresponding structural alterations in the adult human brain, and examined whether such time lags between functional and structural connectivity changes are affected by functional differences between different large-scale brain networks. Results: In this single-case study, we report that, compared to attention-related networks, functional connectivity changes in default-mode, fronto-parietal, and sensory-related networks occurred in advance of modulations of the corresponding structural connectivity with significantly longer time lags. In particular, the longest time lags were observed in sensory-related networks. In contrast, such significant temporal differences in connectivity change were not seen in comparisons between anatomically categorised different brain areas, such as frontal and occipital lobes. These observations survived even after multiple validation analyses using different connectivity definitions or using parts of the datasets. Conclusions: Although the current findings should be examined in independent datasets with different demographic background and by experimental manipulation, this single-case study indicates the possibility that plasticity of macroscopic brain networks could be affected by cognitive and perceptual functions implemented in the networks, and implies a hierarchy in the plasticity of functionally different brain systems.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Objectives: Evidence from animal studies suggests that aerobic exercise may promote neuroplasticity and could, therefore, provide therapeutic benefits for neurological diseases such as multiple sclerosis (MS). However, the effects of exercise in human CNS disorders on the topology of brain networks, which might serve as an outcome at the interface between biology and clinical performance, remain poorly understood.Methods: We investigated functional and structural networks in patients with relapsing-remitting MS in a clinical trial of standardized aerobic exercise. Fifty-seven patients were randomly assigned to moderate-intensity exercise for 3 months or a non-exercise control group. We reconstructed functional networks based on resting-state functional magnetic resonance imaging (MRI) and used probabilistic tractography on diffusion-weighted imaging data for structural networks.Results: At baseline, compared to 30 healthy controls, patients exhibited decreased structural connectivity that was most pronounced in hub regions of the brain. Vice versa, functional connectivity was increased in hubs. After 3 months, we observed hub independent increased functional connectivity in the exercise group while the control group presented a loss of functional hub connectivity. On a structural level, the control group remained unchanged, while the exercise group had also increased connectivity. Increased clustering of hubs indicates a better structural integration and internal connectivity at the top of the network hierarchy.Conclusion: Increased functional connectivity of hubs contrasts a loss of structural connectivity in relapsing-remitting MS. Under an exercise condition, a further hub independent increase of functional connectivity seems to translate in higher structural connectivity of the whole brain.

A basic tenet of biological psychiatry is that psychiatric disorders are driven by abnormalities in brain function, which in turn reflect abnormalities in the underlying brain circuits, i.e., in the wiring of the brain. These circuit abnormalities presumably reflect a complex interplay between genes and environment. Many psychiatric disorders have strong genetic underpinnings: common or rare variants of genes, individually or in combination, elevate the susceptibility to disorders such as autism (1), schizophrenia (2), and many others. Most psychiatric disorders are thought to be neurodevelopmental in nature, either because symptoms typically arise during childhood (e.g., autism) or because the interactions between genes and environment begin early, even if the onset of the disorder becomes evident only in adolescence or adulthood. To better understand, diagnose, and treat psychiatric disorders, it is crucial to obtain deeper insights into brain circuits in health and disease and in humans and animal models. Here, we focus on the relevance of human in vivo neuroimaging, particularly involving magnetic resonance imaging (MRI). We briefly address three major points. First, recent neuroimaging studies have already provided important insights about abnormalities related to brain structure, function, and connectivity in psychopathology. Second, recent advances in neuroimaging of healthy adults, including many driven by the Human Connectome Project, offer exciting prospects for accelerated progress in characterizing disease-related brain connectivity abnormalities. Third, methodological limitations of each neuroimaging method, some of which are inadequately appreciated, require critical assessments and careful interpretation of research findings, especially when placed in the context of the extraordinary complexity of brain circuits revealed by studies of laboratory animals.

Changes in structural and functional connectivity among resting-state networks across the human lifespan

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.

Decision letter: Disruption in structural–functional network repertoire and time-resolved subcortical fronto-temporoparietal connectivity in disorders of consciousness

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Structural connectivity (SC) of white matter (WM) and functional connectivity (FC) of cortical regions undergo changes in normal aging. As WM tracts form the underlying anatomical architecture that connects regions within resting state networks (RSNs), it is intuitive to expect that SC and FC changes with age are correlated. Studies that investigated the relationship between SC and FC in normal aging are rare, and have mainly compared between groups of elderly and younger subjects. The objectives of this work were to investigate linear SC and FC changes across the healthy adult lifespan, and to define relationships between SC and FC measures within seven whole-brain large scale RSNs. Diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) data were acquired from 177 healthy participants (male/female = 69/108; aged 18–87 years). Forty cortical regions across both hemispheres belonging to seven template-defined RSNs were considered. Mean diffusivity (MD), fractional anisotropy (FA), mean tract length, and number of streamlines derived from DTI data were used as SC measures, delineated using deterministic tractography, within each RSN. Pearson correlation coefficients of rs-fMRI-obtained BOLD signal time courses between cortical regions were used as FC measure. SC demonstrated significant age-related changes in all RSNs (decreased FA, mean tract length, number of streamlines; and increased MD), and significant FC decrease was observed in five out of seven networks. Among the networks that showed both significant age related changes in SC and FC, however, SC was not in general significantly correlated with FC, whether controlling for age or not. The lack of observed relationship between SC and FC suggests that measures derived from DTI data that are commonly used to infer the integrity of WM microstructure are not related to the corresponding changes in FC within RSNs. The possible temporal lag between SC and FC will need to be addressed in future longitudinal studies to better elucidate the links between SC and FC changes in normal aging.

BackgroundThe goal of this study was to determine whether vascular factors, expressed as the Framingham Stroke Risk Profile (FSRP), and/or tau deposition impact functional brain connectivity within and between functional brain networks i.e. default mode, frontoparietal, dorsal attention, and ventral attention networks. Regional blood flow measured by fMRI has been used to infer functional brain connectivity. Regions with synchronized blood flow are thought to be functionally connected while areas that have desynchronized blood flow are thought to be less functionally connected. Factors such as age have been linked to a reduction in functional connectivity.Method224 participants (mean age 54±8, 56% men) from the third generation of the Framingham Heart Study were imaged at Boston University from September 2015 to August 2018. Each participant had a high resolution MPRAGE T1 and a seven‐minute resting state fMRI scan. The T1 scans were processed using Freesurfer v6.0 and the resting state fMRI scans with FSL. Functional networks were constructed using the Yeo 7 network atlas (Yeo, 2011). Correlations within and between the functional brain networks were generated and z corrected. The relationship between FSRP, regional amyloid using the Pittsburgh B ligand, tau deposition using Flortaucipir, and functional connectivity were assessed using linear regression models adjusted for age, sex and interval between FSRP (or amyloid and tau) measurements and fMRI.ResultVascular risk factors and tau deposition had opposite impacts on functional connectivity. Increases in the FSRP were linked to increased functional connectivity between the default mode and visual networks, as well as the frontoparietal. Conversely, tau deposition in the inferior temporal, precuneus, and entorhinal cortices was linked to a reduction in functional connectivity within the frontoparietal network, between the default mode and somatomotor, and dorsal attention and somatomotor networks.ConclusionVascular risk factors appear to relate to an enhancement of functional connectivity while regional tau deposition appears to have an adverse impact on both within and between network connectivity. It is plausible that these changes in functional connectivity represent a compensatory response in the brain to alterations in vascular function and the presence of neuropathology in order to maintain cognitive abilities.

The structural–functional connectome and the default mode network of the human brain

Here we document cortical neural connectivity changes associated with several weeks of prosthetic use in an individual with bilateral upper-limb congenital amputation. Secondly, we explore how those changes relate to prosthetic performance over time. Previous research in unilateral aplasia has shown that functional brain connectivity and activations can be disrupted in the missing hand area, and that prosthetic use can normalize those abnormalities. Functional connectivity and prosthetic use related brain changes in individuals with bilateral congenital upper limb amputations have not been defined. Here, we describe functional and structural connectivity changes measured with MRI after 10-weeks' unilateral use of an sEMG-controlled virtual prosthetic in an individual with aplasia born without either arm. We find that both functional connectivity and structural connectivity change with sEMG prosthetic use. Specifically, functional connectivity of motor regions tends to lateralize and become more hemisphere specific. Additionally, structural connectivity of motor cortico-spinal white matter projections and interhemispheric commissural projections increase after sEMG prosthetic use. These functional connectivity changes are different from those previously reported for one-handed congenital amputees, where prosthetic use normalized, not lateralized, imbalanced interhemispheric motor connectivity. Alongside these neural changes, sEMG virtual prosthetic performance both increased and decreased over time, depending on the action performed. Our results suggest that neural representations of bilateral congenital amputation and subsequent neural adaptions with unilateral prosthetic use may be distinct from those of unilateral congenital and traumatic upper-limb amputees. Consideration of condition-specific neurobiology may be critical in developing effective neuro-prostheses.Clinical Relevance- This describes the neural changes induced by sEMG prosthetic control in a congenital bilateral amputee.