Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization.

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions. We applied laser speckle imaging, ultrafast ultrasound, and two-photon microscopy in a thrombin-based mouse model of stroke and fibrinolytic treatment to show that LMCs maintain cerebral autoregulation and allow for gradual reperfusion, resulting in small infarcts. In mice with poor LMCs, distal arterial segments collapse, and deleterious hyperemia causes hemorrhage and mortality after recanalization. In silico analyses confirm the relevance of LMCs for preserving perfusion in the ischemic region. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion and preventing futile recanalization after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for beneficial reperfusion after stroke.

Impaired drainage through capillary-venous networks contributes to age-related white matter loss.

The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We used in vivo deep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region of white matter in the mouse brain. We show that these deep tissues are exclusively drained by sparse and wide-reaching venules, termed principal cortical venules, which mirror vascular architecture at the human cortical-U fiber interface. During aging, capillary networks draining into deep branches of principal cortical venules are selectively constricted, reduced in density, and diminished in pericyte numbers. This causes hypo-perfusion in deep tissues, and correlates with gliosis and demyelination, whereas superficial tissues become relatively hyper-perfused. Thus, age-related impairment of capillary-venular drainage is a key vascular deficit that contributes to the unique vulnerability of cerebral white matter during brain aging.

The role of leptomeningeal collaterals in redistributing blood flow during stroke.

Leptomeningeal collaterals (LMCs) connect the main cerebral arteries and provide alternative pathways for blood flow during ischaemic stroke. This is beneficial for reducing infarct size and reperfusion success after treatment. However, a better understanding of how LMCs affect blood flow distribution is indispensable to improve therapeutic strategies. Here, we present a novel in silico approach that incorporates case-specific in vivo data into a computational model to simulate blood flow in large semi-realistic microvascular networks from two different mouse strains, characterised by having many and almost no LMCs between middle and anterior cerebral artery (MCA, ACA) territories. This framework is unique because our simulations are directly aligned with in vivo data. Moreover, it allows us to analyse perfusion characteristics quantitatively across all vessel types and for networks with no, few and many LMCs. We show that the occlusion of the MCA directly caused a redistribution of blood that was characterised by increased flow in LMCs. Interestingly, the improved perfusion of MCA-sided microvessels after dilating LMCs came at the cost of a reduced blood supply in other brain areas. This effect was enhanced in regions close to the watershed line and when the number of LMCs was increased. Additional dilations of surface and penetrating arteries after stroke improved perfusion across the entire vasculature and partially recovered flow in the obstructed region, especially in networks with many LMCs, which further underlines the role of LMCs during stroke.

Assessing cognitive changes in multiple sclerosis: criteria for a reliable decision.

INTRODUCTION: Quantifying a significant cognitive change on a neuropsychological battery is essential to assess patients' decline or recovery and offer appropriate care. The reliability of change indices is particularly important in multiple sclerosis (MS), as the course of cognitive impairment is quite unpredictable, due at least in part to substantial interindividual variability. The main objective of this study was to compare six different methods for assessing cognitive change in an MS sample: the SD method, two reliable change indices, two standardized regression-based methods (SRB), and the generalized regression-based method (GSRB). METHOD: One hundred and twenty-three patients with clinically definite MS and 89 healthy controls underwent a battery of standardized neuropsychological tests assessing cognitive functions that are frequently affected in this disease (i.e., verbal episodic memory, working memory, processing speed and verbal fluency). RESULTS: We observed fairly similar proportions of improvement, decline or stability in the control group whatever the method. By contrast, in the MS sample, regression-based methods with one predictor (i.e., score at T1) and four predictors (i.e., score at T1 and demographic factors: age, sex, education level) detected a significant worsening more often than the reliable change indices while the GSRB method was more consistent with the RCI methods in tasks associated with ceiling effects. CONCLUSIONS: The interpretation of a patient's cognitive changes depends on which method is used. The (G)SRB methods appear to be relevant indicators for assessing cognitive change in MS. The addition of demographic factors does not seem to play an important role in the prediction of significant worsening in the MS sample, regardless of cognitive domain. For clinicians, an easy-to-use free shiny app is provided.

Brain-derived neurotrophic factor Val66Met polymorphism moderates the relationship between impulsivity, negative emotions, and binge drinking intensity in university students.

Studies on the genetic factors involved in binge drinking (BD) and its associated traits are very rare. The aim of this cross-sectional study was to investigate differences in the association between impulsivity, emotion regulation and BD in a sample of young adults according to the rs6265/Val66Met variant in the brain-derived neurotrophic factor (BDNF) gene, a well-known candidate gene in alcohol use disorders. We recruited 226 university students (112 women), aged between 18 and 25 years old, from two centers in France. The participants completed measures related to alcohol consumption, depression severity, state anxiety levels, impulsivity (UPPS-P), and difficulties in emotion regulation [Difficulty in Emotion Regulation Scale (DERS)]. The relationship between the BD score and the clinical characteristics in the BDNF genotype groups was assessed by partial correlation analyses and moderation analyses. The partial correlation analyses showed that, in the Val/Val genotype group, the BD score was positively related to UPPS-P Lack of Premeditation and Sensation Seeking scores. In the Met carriers group, the BD score was positively related to UPPS-P Positive Urgency, lack of Premeditation, lack of Perseverance and Sensation Seeking scores and to Clarity score of the DERS. Moreover, the BD score was positively associated with depression severity and state anxiety scores. The moderation analyses revealed that BDNF Val/Met genotype moderated the relationship between several clinical variables and BD. The results of the present study support the hypothesis of common and specific vulnerability factors regarding impulsivity and emotion regulation difficulties associated with BD according to this BDNF rs6265 polymorphism.

Facial emotion recognition processes according to schizotypal personality traits: An eye-tracking study.

Facial emotion recognition has been shown to be impaired among patients with schizophrenia and, to a lesser extent, among individuals with high levels of schizotypal personality traits. However, aspects of gaze behavior during facial emotion recognition among the latter are still unclear. This study therefore investigated the relations between eye movements and facial emotion recognition among nonclinical individuals with schizotypal personality traits. A total of 83 nonclinical participants completed the Schizotypal Personality Questionnaire (SPQ) and performed a facial emotion recognition task. Their gaze behavior was recorded by an eye-tracker. Self-report questionnaires measuring anxiety, depressive symptoms, and alexithymia were administered. At the behavioral level, correlation analyses showed that higher SPQ scores were associated with lower surprise recognition accuracy scores. Eye-tracking data revealed that higher SPQ scores were associated with shorter dwell time on relevant facial features during sadness recognition. Regression analyses revealed that the total SPQ score was the only significant predictor of eye movements during sadness recognition, and depressive symptoms were the only significant predictor of surprise recognition accuracy. Furthermore, dwell time predicted response times for sadness recognition in that shorter dwell time on relevant facial features was associated with longer response times. Schizotypal traits may be associated with decreased attentional engagement in relevant facial features during sadness recognition and impede participants' response times. Slower processing and altered gaze patterns during the processing of sad faces could lead to difficulties in everyday social situations in which information must be rapidly processed to enable the successful interpretation of other people's behavior.

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure.

Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. Here, we conduct cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induces capillary dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated in the aged brain, and result in increased flow heterogeneity in capillary networks. A subset of affected capillaries experience reduced perfusion due to flow steal. Some capillaries stall in flow and regress, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restores endothelial coverage and vascular tone within days. Pericyte remodeling is slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.

Faux Pas Recognition and Executive Processes in Patients with Alcohol Use Disorder: Toward an Investigation of Interindividual Heterogeneity.

OBJECTIVE: Impairment of executive functions (EF) has been documented for decades in patients with alcohol use disorders (AUD), while more recent studies have also reported impaired theory of mind. Both have been associated with negative outcomes, particularly a high risk of relapse. However, the interrelatedness of EF and theory of mind impairments remains subject to debate. METHOD: About 19 AUD outpatients and 20 healthy controls (HC) were asked to complete measures of motor inhibition, mental flexibility, and updating to assess EF, and the faux pas test to assess theory of mind. RESULTS: As expected, patients' mean performances on EF and faux pas measures were poorer than those of HC. Correlational analyses revealed that executive processes were differentially related to faux pas subscores. Additional single-case analyses corroborated the strong association between EF and faux pas interpretation, as patients with AUD mostly had congruent performances (i.e., both EF and faux pas impaired or both EF and faux pas preserved). CONCLUSIONS: This study highlights the interrelatedness of EF and faux pas performances in AUD, but also emphasizes the incomplete overlap of the cognitive processes involved in these tasks, with heterogeneous patterns of association. Based on these findings, tailored cognitive rehabilitation programs that simultaneously target EF and faux pas recognition could be developed to favor patients' social inclusion and reduce the risk of relapse. Results also argue in favor of systematic screening for EF and theory of mind impairments among AUD patients.

The severity of microstrokes depends on local vascular topology and baseline perfusion.

Cortical microinfarcts are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of blood flow disturbance has not yet been identified. We employed blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single-capillary occlusions. Our simulations reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in perfusion are observed in capillaries with two inflows and two outflows. This specific topological configuration only occurs with a frequency of 8%. The majority of capillaries have one inflow and one outflow and is likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes bear potential to induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally.

A blockage in one of the tiny blood vessels or capillaries of the brain causes a 'microstroke'. Microstrokes do not cause the same level of damage as a major stroke, which is caused by a blockage in a larger blood vessel that completely cuts off oxygen to a part of the brain for a period. But microstrokes do increase the risk of developing conditions like dementia ­ including Alzheimer's disease ­ later in life. People with these neurodegenerative conditions have fewer capillaries in their brains. The capillaries make up a mesh-like network of millions of vessels that supply most of the energy and oxygen to the brain. Repeated microstrokes may contribute to progressive loss of capillaries over time. Reduced numbers of capillaries may increase memory loss and other brain difficulties. To better understand how microstrokes affect blood flow in the brain, Schmid et al. created a computer model to simulate blood flow in capillaries in the mouse brain. Then, they modeled what happens to the blood flow when one capillary is blocked. The experiments showed that the configuration of the blocked capillary determines how much blood flow in neighboring capillaries changes. Blockages in capillaries with two vessels feeding in and two vessels feeding out caused the greatest blood flow disturbances. But these 2-in-2-out vessels only make up about 8% of all brain capillaries. Blockages in capillaries with different configurations with respect to feeding vessels had less effect. The experiments suggest that most microstrokes have limited effects on blood flow on the scale of the entire brain because of redundancies in the capillary network in the brain. However, the ability of the capillary network to adapt and reroute blood flow in response to small blockages may decrease with aging. Over time, ministrokes in a single capillary may set off a chain reaction of disturbed blood flow and more blockages. This may decrease energy and oxygen supplies explaining age- and disease-related brain decline. Better understanding the effects of microstrokes on blood flow may help scientists develop new ways to prevent such declines.

Simulation of intravoxel incoherent perfusion signal using a realistic capillary network of a mouse brain.

PURPOSE: To simulate the intravoxel incoherent perfusion magnetic resonance magnitude signal from the motion of blood particles in three realistic vascular network graphs from a mouse brain. METHODS: In three networks generated from the cortex of a mouse scanned by two-photon laser microscopy, blood flow in each vessel was simulated using Poiseuille's law. The trajectories, flow speeds and phases acquired by a fixed number of simulated blood particles during a Stejskal-Tanner bipolar pulse gradient scheme were computed. The resulting magnitude signal was obtained by integrating all phases and the pseudo-diffusion coefficient D* was estimated by fitting an exponential signal decay. To better understand the anatomical source of the intravoxel incoherent motion (IVIM) perfusion signal, the above was repeated restricting the simulation to various types of vessel. RESULTS: The characteristics of the three microvascular networks were respectively vessel lengths (mean ± std. dev.) 67.2 ± 53.6 µm, 59.8 ± 46.2 µm and 64.5 ± 50.9 µm, diameters 6.0 ± 3.5 µm, 5.7 ± 3.6 µm and 6.1 ± 3.7 µm and simulated blood velocity 0.9 ± 1.7 µm/ms, 1.4 ± 2.5 µm/ms and 0.7 ± 2.1 µm/ms. Exponential fitting of the simulated signal decay as a function of b-value resulted in the following D*-values [10-3 mm2 /s]: 31.7, 40.4 and 33.4. The signal decay for low b-values was the largest in the larger vessels, but the smaller vessels and the capillaries accounted for more of the total volume of the networks. CONCLUSION: This simulation improves the theoretical understanding of the IVIM perfusion estimation method by directly linking the MR IVIM perfusion signal to an ultra-high resolution measurement of the microvascular network and a realistic blood flow simulation.

Heterogeneity of Executive Function Abilities in Recently Detoxified Patients with Alcohol Use Disorder: Evidence from a Cluster Analysis.

BACKGROUND: Impairments of executive functions (EF) have been consistently reported in patients with alcohol use disorder (AUD), mostly in studies which were based on comparisons of means between groups. However, given the high heterogeneity in AUD patients, this approach could actually cover a wide range of EF patterns. In the present study, we addressed the paucity of the literature about cognitive heterogeneity in AUD by applying a cluster analytical approach on EF measures. METHODS: Seventy-eight withdrawn AUD patients and 77 healthy Control participants completed measures targeting a variety of EF components. We then used cluster analysis to identify subgroups of AUD patients. Furthermore, the AUD subgroups were compared to the Control group to establish their specific EF patterns. RESULTS: Findings showed that AUD patients could be divided into 3 clusters based on their EF performances. A first cluster accounting for half of the AUD sample was characterized by unimpaired EF (Cluster 1). The 2 other clusters displayed major EF deficits but differed regarding the deficient EF component. While Cluster 2 was mainly impaired on measures of rule deduction and mental flexibility, Cluster 3 was mainly characterized by a lower processing speed and impaired inhibition of an ongoing motor response. Differences in EF performances of AUD patients could be related to differences in premorbid cognitive reserve, impulsiveness patterns, and withdrawal complications. CONCLUSIONS: This study highlights the importance of the cognitive heterogeneity in AUD by showing that AUD patients display substantially different EF patterns. Future studies should try to go beyond mere group comparisons to further deepen our understanding about cognitive differences between AUD patients. In the long run, this could lead to more personalized prevention and treatment programs specifically tailored to the patient's impairments.

Component process analysis of verbal memory in a sample of students with a binge drinking pattern.

BACKGROUND: Many studies have emphasized the harmful impact of binge drinking on several cognitive functions, including memory. However, the exact nature of the memory processes involved is still unknown. The present study was designed to assess verbal working memory and verbal episodic memory, especially its encoding, storage and retrieval processes, in binge drinking to identify the processes impacted by this behavior. METHODS: Participants were 48 community-recruited college students aged 18-25 years and categorized as either binge drinkers (BDs) or social drinkers (SDs). They were assessed with (a) subtests of the Wechsler scale (digit span, letter-number sequencing) measuring verbal working memory, and (b) a modified version of the Free and Cued Selective Reminding Test (FCSRT), which measures verbal episodic memory functioning in various conditions of encoding (controlled) and recollection (free recall, cued recall, and recognition). RESULTS: Verbal working memory was unaffected by binge drinking, whereas verbal episodic memory performances were reduced. In particular, analysis of the modified FCSRT scores suggested that BDs had less proficient storage and retrieval processes. Furthermore, correlational analyses indicated that the proficiency of these memory components was negatively correlated with several indicators of binge drinking behavior. CONCLUSIONS: Results suggest that binge drinking behavior affects the storage and recollection processes of verbal episodic memory. The academic failure described in binge drinkers could be partly related to this harmful effect. Our results on the negative impact of binge drinking on memory should be used to develop information campaigns targeting students.

Predicting Vessel Diameter Changes to Up-Regulate Biphasic Blood Flow During Activation in Realistic Microvascular Networks.

A dense network of blood vessels distributes blood to different regions of the brain. To meet the temporarily and spatially varying energy demand resulting from changes in neuronal activity, the vasculature is able to locally up-regulate the blood supply. However, to which extent diameter changes of different vessel types contribute to the up-regulation, as well as the spatial and temporal characteristics of their changes, are currently unknown. Here, we present a new simulation method, which solves an inverse problem to calculate diameter changes of individual blood vessels needed to achieve predefined blood flow distributions in microvascular networks. This allows us to systematically compare the impact of different vessel types in various regulation scenarios. Moreover, the method offers the advantage that it handles the stochastic nature of blood flow originating from tracking the movement of individual red blood cells. Since the inverse problem is formulated for time-averaged pressures and flow rates, a deterministic approach for calculating the diameter changes is used, which allows us to apply the method for large realistic microvascular networks with high-dimensional parameter spaces. Our results obtained in both artificial and realistic microvascular networks reveal that diameter changes at the level of capillaries enable a very localized regulation of blood flow. In scenarios where only larger vessels, i.e., arterioles, are allowed to adapt, the flow increase cannot be confined to a specific activated region and flow changes spread into neighboring regions. Furthermore, relatively small dilations and constrictions of all vessel types can lead to substantial changes of capillary blood flow distributions. This suggests that small scale regulation is necessary to obtain a localized increase in blood flow.

Red blood cells stabilize flow in brain microvascular networks.

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term "well-balanced bifurcations". Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 µm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.

Vascular density and distribution in neocortex.

An amazingly wide range of complex behavior emerges from the cerebral cortex. Much of the information processing that leads to these behaviors is performed in neocortical circuits that span throughout the six layers of the cortex. Maintaining this circuit activity requires substantial quantities of oxygen and energy substrates, which are delivered by the complex yet well-organized and tightly-regulated vascular system. In this review, we provide a detailed characterization of the most relevant anatomical and functional features of the cortical vasculature. This includes a compilation of the available data on laminar variation of vascular density and the topological aspects of the microvascular system. We also review the spatio-temporal dynamics of cortical blood flow regulation and oxygenation, many aspects of which remain poorly understood. Finally, we discuss some of the important implications of vascular density, distribution, oxygenation and blood flow regulation for (laminar) fMRI.

Depth-dependent flow and pressure characteristics in cortical microvascular networks.

A better knowledge of the flow and pressure distribution in realistic microvascular networks is needed for improving our understanding of neurovascular coupling mechanisms and the related measurement techniques. Here, numerical simulations with discrete tracking of red blood cells (RBCs) are performed in three realistic microvascular networks from the mouse cerebral cortex. Our analysis is based on trajectories of individual RBCs and focuses on layer-specific flow phenomena until a cortical depth of 1 mm. The individual RBC trajectories reveal that in the capillary bed RBCs preferentially move in plane. Hence, the capillary flow field shows laminar patterns and a layer-specific analysis is valid. We demonstrate that for RBCs entering the capillary bed close to the cortical surface (< 400 µm) the largest pressure drop takes place in the capillaries (37%), while for deeper regions arterioles are responsible for 61% of the total pressure drop. Further flow characteristics, such as capillary transit time or RBC velocity, also vary significantly over cortical depth. Comparison of purely topological characteristics with flow-based ones shows that a combined interpretation of topology and flow is indispensable. Our results provide evidence that it is crucial to consider layer-specific differences for all investigations related to the flow and pressure distribution in the cortical vasculature. These findings support the hypothesis that for an efficient oxygen up-regulation at least two regulation mechanisms must be playing hand in hand, namely cerebral blood flow increase and microvascular flow homogenization. However, the contribution of both regulation mechanisms to oxygen up-regulation likely varies over depth.

The impact of capillary dilation on the distribution of red blood cells in artificial networks.

Recent studies suggest that pericytes around capillaries are contractile and able to alter the diameter of capillaries. To investigate the effects of capillary dilation on network dynamics, we performed simulations in artificial capillary networks of different sizes and complexities. The unequal partition of hematocrit at diverging bifurcations was modeled by assuming that each red blood cell (RBC) enters the branch with the faster instantaneous flow. Network simulations with and without RBCs were performed to investigate the effect of local dilations. The results showed that the increase in flow rate due to capillary dilation was less when the effects of RBCs are included. For bifurcations with sufficient RBCs in the parent vessel and nearly equal flows in the branches, the flow rate in the dilated branch did not increase. Instead, a self-regulation of flow was observed due to accumulation of RBCs in the dilated capillary. A parametric study was performed to examine the dependence on initial capillary diameter, dilation factor, and tube hematocrit. Furthermore, the conditions needed for an efficient self-regulation mechanism are discussed. The results support the hypothesis that RBCs play a significant role for the fluid dynamics in capillary networks and that it is crucial to consider the blood flow rate and the distribution of RBCs to understand the supply of oxygen in the vasculature. Furthermore, our results suggest that capillary dilation/constriction offers the potential of being an efficient mechanism to alter the distribution of RBCs locally and hence could be important for the local regulation of oxygen delivery.