Functional connectivity changes in cerebral small vessel disease - a systematic review of the resting-state MRI literature.

BACKGROUND: Cerebral small vessel disease (CSVD) is a common neurological disease present in the ageing population that is associated with an increased risk of dementia and stroke. Damage to white matter tracts compromises the substrate for interneuronal connectivity. Analysing resting-state functional magnetic resonance imaging (fMRI) can reveal dysfunctional patterns of brain connectivity and contribute to explaining the pathophysiology of clinical phenotypes in CSVD. MATERIALS AND METHODS: This systematic review provides an overview of methods and results of recent resting-state functional MRI studies in patients with CSVD. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol, a systematic search of the literature was performed. RESULTS: Of 493 studies that were screened, 44 reports were identified that investigated resting-state fMRI connectivity in the context of cerebral small vessel disease. The risk of bias and heterogeneity of results were moderate to high. Patterns associated with CSVD included disturbed connectivity within and between intrinsic brain networks, in particular the default mode, dorsal attention, frontoparietal control, and salience networks; decoupling of neuronal activity along an anterior-posterior axis; and increases in functional connectivity in the early stage of the disease. CONCLUSION: The recent literature provides further evidence for a functional disconnection model of cognitive impairment in CSVD. We suggest that the salience network might play a hitherto underappreciated role in this model. Low quality of evidence and the lack of preregistered multi-centre studies remain challenges to be overcome in the future.

Game theoretical mapping of white matter contributions to visuospatial attention in stroke patients with hemineglect.

White matter bundles linking gray matter nodes are key anatomical players to fully characterize associations between brain systems and cognitive functions. Here we used a multivariate lesion inference approach grounded in coalitional game theory (multiperturbation Shapley value analysis, MSA) to infer causal contributions of white matter bundles to visuospatial orienting of attention. Our work is based on the characterization of the lesion patterns of 25 right hemisphere stroke patients and the causal analysis of their impact on three neuropsychological tasks: line bisection, letter cancellation, and bells cancellation. We report that, out of the 11 white matter bundles included in our MSA coalitions, the optic radiations, the inferior fronto-occipital fasciculus and the anterior cingulum were the only tracts to display task-invariant contributions (positive, positive, and negative, respectively) to the tasks. We also report task-dependent influences for the branches of the superior longitudinal fasciculus and the posterior cingulum. By extending prior findings to white matter tracts linking key gray matter nodes, we further characterize from a network perspective the anatomical basis of visual and attentional orienting processes. The knowledge about interactions patterns mediated by white matter tracts linking cortical nodes of attention orienting networks, consolidated by further studies, may help develop and customize brain stimulation approaches for the rehabilitation of visuospatial neglect.

Cortical thickness and cognitive performance in asymptomatic unilateral carotid artery stenosis.

BACKGROUND: We investigated changes of cortical thickness and its association with cognitive performance in patients with high-grade carotid artery stenosis without ischemic brain lesions. METHODS: We studied 25 patients with unilateral carotid artery stenosis ≥50% and 25 age-matched controls. All subjects underwent T1-weighted MRI, and cortical thickness was measured in 33 regions of interest in each hemisphere, as well as in brain regions belonging to the vascular territory of the middle cerebral artery (MCA). General linear mixed models were fitted to the dependent variable cortical thickness. Cognitive assessment comprised the Stroop Test and Trail Making Test B. RESULTS: In the linear mixed model, presence of carotid stenosis had no effect on cortical thickness. There was a significant interaction of stenosis and region with a trend towards lower cortical thickness in the MCA region on the side of carotid stenosis. Patients with carotid stenosis performed significantly worse on the Stroop test than controls, but there was no correlation with cortical thickness. CONCLUSION: In patients with carotid stenosis without ischemic brain lesions, neither a clear pattern of reduced cortical thickness nor an association of cortical thickness with cognitive function was observed. Our data do not support the hypothesized association of cortical thinning and cognitive impairment in carotid stenosis.

Is white matter more prone to diffusion lesion reversal after thrombolysis?

BACKGROUND AND PURPOSE: In acute ischemic stroke, white matter (WM) is considered more resistant to infarction than gray matter (GM). To test this hypothesis, we compared the fate of WM and GM voxels belonging to the acute diffusion-weighted imaging (DWI) lesion, expecting WM voxels to be more prone to reversal after thrombolysis. METHODS: Reversible acute DWI (RAD) lesion was defined voxel-wise as an acute lesion on initial DWI (DWI1) with no visible lesion on 24-hour DWI (DWI2). Only patients with RAD lesions >10 mL and >10% of DWI1 from our previously reported cohort were eligible. The core was defined as voxels hyperintense on DWI1 and DWI2. Semiautomated segmentation of DWI1, core, and RAD lesions, normalization into standard space, and WM/GM segmentation allowed calculations of WM/GM proportions in each region of interest using a voxel-counting algorithm. RESULTS: Thirty patients were eligible (RAD lesion median volume [interquartile range], 23.3 mL [19.1-35.0 mL]; onset-to-treatment time, 134 minutes [105-185 minutes]). WM voxels fraction was greater in RAD lesions than in the core (59.4% [52.8%-68.9%] versus 49.6% [43.0%-57.5%]; P=0.011). The proportion of reversibility was greater for WM than for GM voxels (60.8% [25.5%-88.7%] versus 53.5% [21.1%-77.3%]; P=0.02). The percentage of RAD lesions increased with the proportion of WM present in the acute DWI lesion (P<0.0001; R=0.67). CONCLUSIONS: Acute DWI lesions predominantly involving WM may be more prone to reversal and, hence, to respond to therapy than their GM counterparts.

Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a clinically heterogeneous disorder with poor known pathophysiology. Recent neuropathological and structural neuroimaging data pointed to the dysfunction of cortico-basal ganglia networks. Nonetheless, it is not clear how these structural changes alter the functional activity of the brain and lead to heterogeneous clinical expressions of the syndrome. The objective of this study was to evaluate global integrative state and organization of functional connections of sensori-motor, associative and limbic cortico-basal ganglia networks, which are likely involved in tics and behavioural expressions of Gilles de la Tourette syndrome. We also tested the hypothesis that specific regions and networks contribute to different symptoms. Data were acquired on 59 adult patients and 27 gender- and age-matched controls using a 3T magnetic resonance imaging scanner. Cortico-basal ganglia networks were constructed from 91 regions of interest. Functional connectivity was quantified using global integration and graph theory measures. We found a stronger functional integration (more interactions among anatomical regions) and a global functional disorganization of cortico-basal ganglia networks in patients with Gilles de la Tourette syndrome compared with controls. All networks were characterized by a shorter path length, a higher number of and stronger functional connections among the regions and by a loss of pivotal regions of information transfer (hubs). The functional abnormalities correlated to tic severity in all cortico-basal ganglia networks, namely in premotor, sensori-motor, parietal and cingulate cortices and medial thalamus. Tic complexity was correlated to functional abnormalities in sensori-motor and associative networks, namely in insula and putamen. Severity of obsessive-compulsive disorder was correlated with functional abnormalities in associative and limbic networks, namely in orbito-frontal and prefrontal dorsolateral cortices. The results suggest that the pattern of functional changes in cortico-basal ganglia networks in patients could reflect a defect in brain maturation. They also support the hypothesis that distinct regions of cortico-basal ganglia networks contribute to the clinical heterogeneity of this syndrome.

Total mismatch in anterior circulation stroke patients before thrombolysis.

BACKGROUND AND PURPOSE: Our aim was to estimate the prevalence of negative diffusion-weighted imaging (DWI) with total perfusion-diffusion mismatch in a large series of anterior circulation stroke patients treated with thrombolysis and to describe the characteristics of these patients. MATERIALS AND METHODS: From January 2006 to December 2010, a retrospective search was made for total perfusion-diffusion (PWI-DWI) mismatch patterns on pretreatment 1.5-T MRI scans of 166 consecutive thrombolyzed patients taken<4.5 h after onset of anterior stroke. A total mismatch profile corresponded to an absence of initial DWI signal changes with hypoperfusion (T(max)>6 s) on PWI. Clinical and MRI characteristics were compared between DWI+ and DWI- patients. RESULTS: Five (3%) patients had a normal initial DWI. All had stable substantial clinical deficits (NIHSS scores ≥ 6) and large perfusion abnormalities - in other words, 'total mismatch' - and infarcts in the acutely hypoperfused area on follow-up imaging. While DWI- and DWI+ patients did not significantly differ in any of the pretreatment imaging or clinical variables except for the extent of PWI-DWI mismatch, DWI- patients had lower NIHSS scores at 24 h, and were more likely to show early neurological improvement (Δ0-24 h NIHSS ≥ 8) and good outcomes (mRS ≤ 2) at the time of hospital discharge. CONCLUSION: Total mismatch i.e. failure of DWI to reveal any ischemic tissue despite a large perfusion defect, can be observed before thrombolysis even in stroke patients with stable substantial neurological deficits. However, this rare MRI profile is associated with a favorable outcome after thrombolysis.

Intrinsic functional brain connectivity is resilient to chronic hypoperfusion caused by unilateral carotid artery stenosis.

INTRODUCTION: Chronic cerebral hypoperfusion caused by asymptomatic high-grade stenosis of the internal carotid artery (ICA) has been associated with impaired cognitive function. Only few studies exist on underlying changes of functional connectivity (FC). METHODS: 20 patients with unilateral high-grade ICA stenosis without MRI lesions and 25 aged-match controls underwent resting-state functional MRI (rsfMRI) and neuropsychological assessment. Patients were examined within ten days before and 6-10 weeks after surgical or interventional revascularization of carotid stenosis. We examined mean resting-state FC ipsi- and contralateral to stenosis and network topology using graph-theoretical measures. RESULTS: At baseline, intrahemispheric FC was similar for patients and healthy controls. After revascularization mean FC increased moderately without an effect on network topology. Patients performed worse in TMT B and Stroop test, while performance in global screening tests for dementia (Mini Mental Status Examination, DemTect) were comparable. Test results did not improve after revascularization. CONCLUSION: In our study population, we find no effect of chronic hypoperfusion on FC and global cognitive function, although we observe minor impairments in processing speed and mental flexibility. The subtle increase of FC after revascularization could indicate excessive upregulation after restoration of perfusion. However, it might as well be a coincidental finding due to the limited sample size.

Association of Age and Structural Brain Changes With Functional Connectivity and Executive Function in a Middle-Aged to Older Population-Based Cohort.

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting-state functional magnetic resonance imaging (MRI) (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45-74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four predefined resting state networks (default mode, dorsal, salience, and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness.

Game-theoretical mapping of fundamental brain functions based on lesion deficits in acute stroke.

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks.

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis.

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.

Impact of Lesion Load Thresholds on Alberta Stroke Program Early Computed Tomographic Score in Diffusion-Weighted Imaging.

BACKGROUND AND AIMS: Assessment of ischemic lesions on computed tomography or MRI diffusion-weighted imaging (DWI) using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to guide acute stroke treatment. However, it has never been defined how many voxels need to be affected to label a DWI-ASPECTS region ischemic. We aimed to assess the effect of various lesion load thresholds on DWI-ASPECTS and compare this automated analysis with visual rating. MATERIALS AND METHODS: We analyzed overlap of individual DWI lesions of 315 patients from the previously published predictive value of fluid-attenuated inversion recovery study with a probabilistic ASPECTS template derived from 221 CT images. We applied multiple lesion load thresholds per DWI-ASPECTS region (>0, >1, >10, and >20% in each DWI-ASPECTS region) to compute DWI-ASPECTS for each patient and compared the results to visual reading by an experienced stroke neurologist. RESULTS: By visual rating, median ASPECTS was 9, 84 patients had a DWI-ASPECTS score ≤7. Mean DWI lesion volume was 22.1 (±35) ml. In contrast, by use of >0, >1-, >10-, and >20%-thresholds, median DWI-ASPECTS was 1, 5, 8, and 10; 97.1% (306), 72.7% (229), 41% (129), and 25.7% (81) had DWI-ASPECTS ≤7, respectively. Overall agreement between automated assessment and visual rating was low for every threshold used (>0%: κw = 0.020 1%: κw = 0.151; 10%: κw = 0.386; 20% κw = 0.381). Agreement for dichotomized DWI-ASPECTS ranged from fair to substantial (≤7: >10% κ = 0.48; >20% κ = 0.45; ≤5: >10% κ = 0.528; and >20% κ = 0.695). CONCLUSION: Overall agreement between automated and the standard used visual scoring is low regardless of the lesion load threshold used. However, dichotomized scoring achieved more comparable results. Varying lesion load thresholds had a critical impact on patient selection by ASPECTS. Of note, the relatively low lesion volume and lack of patients with large artery occlusion in our cohort may limit generalizability of these findings.

Cognitive Decline and Reorganization of Functional Connectivity in Healthy Aging: The Pivotal Role of the Salience Network in the Prediction of Age and Cognitive Performances.

Normal aging is related to a decline in specific cognitive processes, in particular in executive functions and memory. In recent years a growing number of studies have focused on changes in brain functional connectivity related to cognitive aging. A common finding is the decreased connectivity within multiple resting state networks, including the default mode network (DMN) and the salience network. In this study, we measured resting state activity using fMRI and explored whether cognitive decline is related to altered functional connectivity. To this end we used a machine learning approach to classify young and old participants from functional connectivity data. The originality of the approach consists in the prediction of the performance and age of the subjects based on functional connectivity by using a machine learning approach. Our findings showed that the connectivity profile between specific networks predicts both the age of the subjects and their cognitive abilities. In particular, we report that the connectivity profiles between the salience and visual networks, and the salience and the anterior part of the DMN, were the features that best predicted the age. Moreover, independently of the age of the subject, connectivity between the salience network and various specific networks (i.e., visual, frontal) predicted episodic memory skills either based on a standard assessment or on an autobiographical memory task, and short-term memory binding. Finally, the connectivity between the salience and the frontal networks predicted inhibition and updating performance, but this link was no longer significant after removing the effect of age. Our findings confirm the crucial role of episodic memory and executive functions in cognitive aging and suggest a pivotal role of the salience network in neural reorganization in aging.

Three-tesla functional MR language mapping: comparison with direct cortical stimulation in gliomas.

OBJECTIVE: To evaluate the accuracy of functional MRI (fMRI) at 3T, as currently used in the preoperative mapping of language areas, compared with direct cortical stimulation (DCS) during awake surgery, in patients with supratentorial gliomas; and to identify clinical, histopathologic,and radiologic factors associated with fMRI/DCS discrepancies. METHODS: Language mapping with fMRI and DCS of 40 consecutive patients with gliomas(24 low-grade, 16 high-grade) in functional areas were retrospectively analyzed. Three block designed tasks were performed during fMRI (letter word generation, category word generation,semantic association). During awake surgery, eloquent areas were mapped using DCS, blinded to fMRI. A site-by-site comparison of the 2 techniques was performed using a cortical grid. fMRI sensitivity and specificity were calculated using DCS as the reference. Associations of clinical,histopathologic, and radiologic features (including relative cerebral blood volume [rCBV] measured with dynamic susceptibility contrast MRI) with fMRI false-positive and false-negative occurrence were assessed using hierarchical logistic regressions. RESULTS: Of 2,114 stimulated cortical sites, 103 were positive for language during DCS. Sensitivity and specificity of language fMRI combining the 3 tasks reached 37.1% (95% confidence interval [CI] 20.7­57.2) and 83.4% (95% CI 77.1­88.3), respectively. Astrocytoma subtype(odds ratio [OR] 2.50 [1.32­4.76]; p 5 0.007), tumor rCBV ,1.5 (OR 2.17 [1.08­4.35]; p 50.03), higher cortical rCBV (OR 2.22 [1.15­4.17]; p 5 0.02), and distance to tumor .1 cm (OR2.46 [1.82­3.32]; p # 0.001) were independently associated with fMRI false-positive occurrence. CONCLUSIONS: There are pitfalls in preoperative fMRI as currently used in preoperative language mapping in glioma patients, made more complicated when high-grade and hyperperfused tumors are evaluated.

Combining spatial independent component analysis with regression to identify the subcortical components of resting-state FMRI functional networks.

Functional brain networks are sets of cortical, subcortical, and cerebellar regions whose neuronal activities are synchronous over multiple time scales. Spatial independent component analysis (sICA) is a widespread approach that is used to identify functional networks in the human brain from functional magnetic resonance imaging (fMRI) resting-state data, and there is now a general agreement regarding the cortical regions involved in each network. It is well known that these cortical regions are preferentially connected with specific subcortical functional territories; however, subcortical components (SC) have not been observed whether in a robust or in a reproducible manner using sICA. This article presents a new method to analyze resting-state fMRI data that enables robust and reproducible association of subcortical regions with well-known patterns of cortical regions. The approach relies on the hypothesis that the time course in subcortical regions is similar to that in cortical regions belonging to the same network. First, sICA followed by hierarchical clustering is performed on cortical time series to extract group functional cortical networks. Second, these networks are complemented with related subcortical areas based on the similarity of their time courses, using an individual general linear model and a random-effect group analysis. Two independent resting-state fMRI datasets were processed, and the SC of both datasets overlapped by 69% to 99% depending on the network, showing the reproducibility and the robustness of our approach. The relationship between SC and functional cortical networks was consistent with functional territories (sensorimotor, associative, and limbic) from an immunohistochemical atlas of the basal ganglia.

Don't be Too Strict with Yourself! Rigid Negative Self-Representation in Healthy Subjects Mimics the Neurocognitive Profile of Depression for Autobiographical Memory.

Autobiographical memory (AM) comprises representation of both specific (episodic) and generic (semantic) personal information. Depression is characterized by a shift from episodic to semantic AM retrieval. According to theoretical models, this process ("overgeneralization"), would be linked to reduced executive resources. Moreover, "overgeneral" memories, accompanied by a negativity bias in depression, lead to a pervasive negative self-representation. As executive functions and AM specificity are also closely intricate among "non-clinical" populations, "overgeneral" memories could result in depressive emotional responses. Consequently, our hypothesis was that the neurocognitive profile of healthy subjects showing a rigid negative self-image would mimic that of patients. Executive functions and self-image were measured and brain activity was recorded, by means of fMRI, during episodic AMs retrieval in young healthy subjects. The results show an inverse correlation, that is, a more rigid and negative self-image produces lower performances in both executive and specific memories. Moreover, higher negative self-image is associated with decreased activity in the left ventro-lateral prefrontal and in the anterior cingulate cortex, repeatedly shown to exhibit altered functioning in depression. Activity in these regions, on the contrary, positively correlates with executive and memory performances, in line with their role in executive functions and AM retrieval. These findings suggest that rigid negative self-image could represent a marker or a vulnerability trait of depression by being linked to reduced executive function efficiency and episodic AM decline. These results are encouraging for psychotherapeutic approaches aimed at cognitive flexibility in depression and other psychiatric disorders.