Large scale assessment of regulatory evolution and transcriptome complexity in mammals

AbstractIn addition to genetic changes affecting the function of gene products, changes in gene expression have been suggested to underlie many or even most of the phenotypic differences among mammals. However, detailed gene expression comparisons were, until recently, restricted to closely related species, owing to technological limitations. Thus, we took advantage of the latest technologies (RNA-Seq) to generate extensive qualitative and quantitative transcriptome data for a unique collection of somatic and germline tissues from representatives of all major mammalian lineages (placental mammals, marsupials and monotremes) and birds, the evolutionary outgroup.In the first major project of my thesis, we performed global comparative analyses of gene expression levels based on these data. Our analyses provided fundamental insights into the dynamics of transcriptome change during mammalian evolution (e.g., the rate of expression change across species, tissues and chromosomes) and allowed the exploration of the functional relevance and phenotypic implications of transcription changes at a genome-wide scale (e.g., we identified numerous potentially selectively driven expression switches).In a second project of my thesis, which was also based on the unique transcriptome data generated in the context of the first project we focused on the evolution of alternative splicing in mammals. Alternative splicing contributes to transcriptome complexity by generating several transcript isoforms from a single gene, which can, thus, perform various functions. To complete the global comparative analysis of gene expression changes, we explored patterns of alternative splicing evolution. This work uncovered several general and unexpected patterns of alternative splicing evolution (e.g., we found that alternative splicing evolves extremely rapidly) as well as a large number of conserved alternative isoforms that may be crucial for the functioning of mammalian organs.Finally, the third and final project of my PhD consisted in analyzing in detail the unique functional and evolutionary properties of the testis by exploring the extent of its transcriptome complexity. This organ was previously shown to evolve rapidly both at the phenotypic and molecular level, apparently because of the specific pressures that act on this organ and are associated with its reproductive function. Moreover, my analyses of the amniote tissue transcriptome data described above, revealed strikingly widespread transcriptional activity of both functional and nonfunctional genomic elements in the testis compared to the other organs. To elucidate the cellular source and mechanisms underlying this promiscuous transcription in the testis, we generated deep coverage RNA-Seq data for all major testis cell types as well as epigenetic data (DNA and histone methylation) using the mouse as model system. The integration of these complete dataset revealed that meiotic and especially post-meiotic germ cells are the major contributors to the widespread functional and nonfunctional transcriptome complexity of the testis, and that this "promiscuous" spermatogenic transcription is resulting, at least partially, from an overall transcriptionally permissive chromatin state. We hypothesize that this particular open state of the chromatin results from the extensive chromatin remodeling that occurs during spermatogenesis which ultimately leads to the replacement of histones by protamines in the mature spermatozoa. Our results have important functional and evolutionary implications (e.g., regarding new gene birth and testicular gene expression evolution).Generally, these three large-scale projects of my thesis provide complete and massive datasets that constitute valuables resources for further functional and evolutionary analyses of mammalian genomes.

What can animal memory study bring to the assessment of memory and cognitive skills for intellectual Disability?

Three case studies are presented to investigate the possibility of evaluating memory and cognitive capacities of severe intellectual disability with attention given to the ecological environment. Two 22-year-old male patients and a 27-year-old male patient, all three with severe intellectual disability with no verbal communication skills, were evaluated with a new and original paradigm adapted to study cognition in humans from experimental paradigms. We developed a test based on animal models to complement the "home" scale of the Adolescent and Adult Psychoeducational Profile (AAPEP), an assessment instrument designed for adolescents and adults with severe developmental disabilities. Results show that the new instrument is helpful, not only to staff members who can better understand the poor performances of their patients in daily life activities but also in the elaboration of individual acquisition plans. These preliminary results demonstrate the interest in developing a larger controlled study and in publishing our procedure.

Resting-State Functional Connectivity Emerges from Structurally and Dynamically Shaped Slow Linear Fluctuations.

Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.

Altered decision-making in multiple sclerosis: a sign of impaired emotional reactivity?

We assessed decision-making capacity and emotional reactivity in 20 patients with multiple sclerosis (MS) and in 16 healthy subjects using the Gambling Task (GT), a model of real-life decision making, and the skin conductance response (SCR). Demographic, neurological, affective, and cognitive parameters were analyzed in MS patients for their effect on decision-making performance. MS patients persisted longer (slope, -3.6%) than the comparison group (slope, -6.4%) in making disadvantageous choices as the GT progressed (p < 0.001), suggesting significant slower learning in MS. Patients with higher Expanded Disability Status Scale scores (EDSS >2.0) showed a different pattern of impairment in the learning process compared with patients with lower functional impairment (EDSS </=2.0). This slower learning was associated with impaired emotional reactivity (anticipatory SCR 3.9 vs 6.1 microSiemens [microS] for patients vs the comparison group, p < 0.0001; post-choice SCR 3.9 vs 6.2 microS, p < 0.0001), but not with executive dysfunction. Impaired emotional dimensions of behavior (assessed using the Dysexecutive Questionnaire, p < 0.002) also correlated with slower learning. Given the considerable consequences that impaired decision making can have on daily life, we suggest that this factor may contribute to handicap and altered quality of life secondary to MS and is dependent on emotional experience. Ann Neurol 2004.

Official Positions for FRAX® clinical regarding rheumatoid arthritis from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Rheumatoid arthritis is the only secondary cause of osteoporosis that is considered independent of bone density in the FRAX(®) algorithm. Although input for rheumatoid arthritis in FRAX(®) is a dichotomous variable, intuitively, one would expect that more severe or active disease would be associated with a greater risk for fracture. We reviewed the literature to determine if specific disease parameters or medication use could be used to better characterize fracture risk in individuals with rheumatoid arthritis. Although many studies document a correlation between various parameters of disease activity or severity and decreased bone density, fewer have associated these variables with fracture risk. We reviewed these studies in detail and concluded that disability measures such as HAQ (Health Assessment Questionnaire) and functional class do correlate with clinical fractures but not morphometric vertebral fractures. One large study found a strong correlation with duration of disease and fracture risk but additional studies are needed to confirm this. There was little evidence to correlate other measures of disease such as DAS (disease activity score), VAS (visual analogue scale), acute phase reactants, use of non-glucocorticoid medications and increased fracture risk. We concluded that FRAX(®) calculations may underestimate fracture probability in patients with impaired functional status from rheumatoid arthritis but that this could not be quantified at this time. At this time, other disease measures cannot be used for fracture prediction. However only a few, mostly small studies addressed other disease parameters and further research is needed. Additional questions for future research are suggested.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data.

Background and Purpose-The safety and efficacy of thrombolysis in cervical artery dissection (CAD) are controversial. The aim of this meta-analysis was to pool all individual patient data and provide a valid estimate of safety and outcome of thrombolysis in CAD.Methods-We performed a systematic literature search on intravenous and intra-arterial thrombolysis in CAD. We calculated the rates of pooled symptomatic intracranial hemorrhage and mortality and indirectly compared them with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. We applied multivariate regression models to identify predictors of excellent (modified Rankin Scale=0 to 1) and favorable (modified Rankin Scale=0 to 2) outcome.Results-We obtained individual patient data of 180 patients from 14 retrospective series and 22 case reports. Patients were predominantly female (68%), with a mean +/- SD age of 46 +/- 11 years. Most patients presented with severe stroke (median National Institutes of Health Stroke Scale score=16). Treatment was intravenous thrombolysis in 67% and intra-arterial thrombolysis in 33%. Median follow-up was 3 months. The pooled symptomatic intracranial hemorrhage rate was 3.1% (95% CI, 1.3 to 7.2). Overall mortality was 8.1% (95% CI, 4.9 to 13.2), and 41.0% (95% CI, 31.4 to 51.4) had an excellent outcome. Stroke severity was a strong predictor of outcome. Overlapping confidence intervals of end points indicated no relevant differences with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register.Conclusions-Safety and outcome of thrombolysis in patients with CAD-related stroke appear similar to those for stroke from all causes. Based on our findings, thrombolysis should not be withheld in patients with CAD. (Stroke. 2011;42:2515-2520.)

An integer-based score to predict functional outcome in acute ischemic stroke: The ASTRAL score.

OBJECTIVE: To develop and validate a simple, integer-based score to predict functional outcome in acute ischemic stroke (AIS) using variables readily available after emergency room admission. METHODS: Logistic regression was performed in the derivation cohort of previously independent patients with AIS (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]) to identify predictors of unfavorable outcome (3-month modified Rankin Scale score >2). An integer-based point-scoring system for each covariate of the fitted multivariate model was generated by their β-coefficients; the overall score was calculated as the sum of the weighted scores. The model was validated internally using a 2-fold cross-validation technique and externally in 2 independent cohorts (Athens and Vienna Stroke Registries). RESULTS: Age (A), severity of stroke (S) measured by admission NIH Stroke Scale score, stroke onset to admission time (T), range of visual fields (R), acute glucose (A), and level of consciousness (L) were identified as independent predictors of unfavorable outcome in 1,645 patients in ASTRAL. Their β-coefficients were multiplied by 4 and rounded to the closest integer to generate the score. The area under the receiver operating characteristic curve (AUC) of the score in the ASTRAL cohort was 0.850. The score was well calibrated in the derivation (p = 0.43) and validation cohorts (0.22 [Athens, n = 1,659] and 0.49 [Vienna, n = 653]). AUCs were 0.937 (Athens), 0.771 (Vienna), and 0.902 (when pooled). An ASTRAL score of 31 indicates a 50% likelihood of unfavorable outcome. CONCLUSIONS: The ASTRAL score is a simple integer-based score to predict functional outcome using 6 readily available items at hospital admission. It performed well in double external validation and may be a useful tool for clinical practice and stroke research.

Use of the Cognitive Performance Scale (CPS) to detect cognitive impairment in the acute care setting: concurrent and predictive validity.

The Cognitive Performance Scale (CPS) was initially designed to assess cognition in long term care residents. Subsequently, the CPS has also been used among in-home, post-acute, and acute care populations even though CPS' clinimetric performance has not been studied in these settings. This study aimed to determine CPS agreement with the Mini Mental Status Exam (MMSE) and its predictive validity for institutionalization and death in a cohort (N=401) of elderly medical inpatients aged 75 years and over. Medical, physical and mental status were assessed upon admission. The same day, the patient's nurse completed the CPS by interview. Follow-up data were gathered from the central billing system (nursing home stay) and proxies (death). Cognitive impairment was present in 92 (23%) patients according to CPS (score >or= 2). Agreement with MMSE was moderate (kappa 0.52, P<.001). Analysis of discordant results suggested that cognitive impairment was overestimated by the CPS in dependent patients with comorbidities and depressive symptoms, and underestimated in older ones. During follow-up, subjects with abnormal CPS had increased risks of death (adjusted hazard ratio (adjHR) 1.7, 95% CI 1.0-2.8, P=.035) and institutionalization (adjHR 2.7, 95% CI 1.3-5.3, P=.006), independent of demographic, health and functional status. Interestingly, subjects with abnormal CPS were at increased risk of death only if they also had abnormal MMSE. The CPS predicted death and institutionalization during follow-up, but correlated moderately well with the MMSE. Combining CPS and MMSE provided additional predictive information, suggesting that domains other than cognition are assessed by professionals when using the CPS in elderly medical inpatients.

EEG-based functional networks in schizophrenia.

Schizophrenia is often considered as a dysconnection syndrome in which, abnormal interactions between large-scale functional brain networks result in cognitive and perceptual deficits. In this article we apply the graph theoretic measures to brain functional networks based on the resting EEGs of fourteen schizophrenic patients in comparison with those of fourteen matched control subjects. The networks were extracted from common-average-referenced EEG time-series through partial and unpartial cross-correlation methods. Unpartial correlation detects functional connectivity based on direct and/or indirect links, while partial correlation allows one to ignore indirect links. We quantified the network properties with the graph metrics, including mall-worldness, vulnerability, modularity, assortativity, and synchronizability. The schizophrenic patients showed method-specific and frequency-specific changes especially pronounced for modularity, assortativity, and synchronizability measures. However, the differences between schizophrenia patients and normal controls in terms of graph theory metrics were stronger for the unpartial correlation method.

J-shaped association between serum glucose and functional outcome in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir ≈7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. METHODS: We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. National Institutes of Health Stroke Scale (NIHSS) score was recorded at 24 hours, and Rankin score was recorded at 3 and 12 months. The association between serum glucose and favorable outcome (Rankin score ≤2) was explored in univariate and multivariate analysis. The model was further analyzed in a robust regression model based on fractional polynomial (-2-2) functions. RESULTS: Serum glucose is independently correlated with functional outcome at 12 months (OR, 1.15; P=0.01). Other predictors of outcome include admission NIHSS score (OR, 1.18; P<0001), age (OR, 1.06; P<0.001), prestroke Rankin score (OR, 20.8; P=0.004), and leukoaraiosis (OR, 2.21; P=0.016). Using these factors in multiple logistic regression analysis, the area under the receiver-operator characteristic curve is 0.869. The association between serum glucose and Rankin score at 12 months is described by a J-shaped curve with a nadir of 5 mmol/L. Glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. A similar curve was generated for the association of glucose and 24-hour NIHSS score, for which glucose values between 4.0 and 7.2 mmol/L are associated with a NIHSS score <7. Discussion-Both hypoglycemia and hyperglycemia are dangerous in acute ischemic stroke as shown by a J-shaped association between serum glucose and 24-hour and 12-month outcome. Initial serum glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome.

Falls efficacy predicts functional status on month after discharge in elderly patients undergoing post-accute rehabilitation

Objective: To investigate the relationship between falls efficacy at admission and functional status reported one month after discharge from post-acute rehabilitation in a cohort of elderly patients. Methods: Participants were elderly patients admitted to postacute rehabilitation in an academic geriatric facility. Data on demographics and affective status were collected upon admission; functional status and gait speed were measured at admission and at discharge; self-reported functional status and history of falls since discharge were collected one month after discharge (follow-up). Falls efficacy was measured using the Fall Efficacy Scale, that assesses confidence in performing 12 activities of daily living without falling (range 0 to 100, higher score indicating higher confidence). Patients were classified using the median FES score at baseline (95) as cut-off to divide the population into "confident" and "fearful" groups. Results: Participants' (N=180, mean age 81.3±7.1 years, 75.6% women) mean FES score was 92.3±8.7 at baseline (range 60-100). Basic ADL score averaged 3.5±1.6 at baseline, 4.7±1.3 at discharge, and 5.5±0.7 at follow-up (self-reported). Baseline FES score was positively correlated with basic ADL at follow-up (rho=0.35, p<.001). At follow-up, 58.7% of the patients were fully independent in basic ADL, this proportion being significantly higher in confident than fearful patients (70.7% vs 42.4%, p<.001). Compared to confident patients, those fearful had significantly lower odds (OR 0.3, 95%CI 0.2-0.6, p<.001) to report full independence at follow-up. This relationship remained (adjOR = 0.4, 95%CI 0.2-0.8, p=.01) after controlling for demographics, baseline gait speed, depressive symptoms, functional status at discharge, and history of falls since discharge. Conclusion: In this cohort of older rehab patients, poor falls efficacy at admission was associated with lower function reported one month after discharge even after controlling for initial mobility performance and functional status at discharge. Further studies should determine whether interventions aiming at falls efficacy improvement will also result in improved function in fearful subjects undergoing rehabilitation.

Mechanisms underlying functional recovery after in vivo focal cerebral ischemia : from preconditioning to diffusion MRI

Version abregée L'ischémie cérébrale est la troisième cause de mort dans les pays développés, et la maladie responsable des plus sérieux handicaps neurologiques. La compréhension des bases moléculaires et anatomiques de la récupération fonctionnelle après l'ischémie cérébrale est donc extrêmement importante et représente un domaine d'intérêt crucial pour la recherche fondamentale et clinique. Durant les deux dernières décennies, les chercheurs ont tenté de combattre les effets nocifs de l'ischémie cérébrale à l'aide de substances exogènes qui, bien que testées avec succès dans le domaine expérimental, ont montré un effet contradictoire dans l'application clinique. Une approche différente mais complémentaire est de stimuler des mécanismes intrinsèques de neuroprotection en utilisant le «modèle de préconditionnement» : une brève insulte protège contre des épisodes d'ischémie plus sévères à travers la stimulation de voies de signalisation endogènes qui augmentent la résistance à l'ischémie. Cette approche peut offrir des éléments importants pour clarifier les mécanismes endogènes de neuroprotection et fournir de nouvelles stratégies pour rendre les neurones et la glie plus résistants à l'attaque ischémique cérébrale. Dans un premier temps, nous avons donc étudié les mécanismes de neuroprotection intrinsèques stimulés par la thrombine, un neuroprotecteur «préconditionnant» dont on a montré, à l'aide de modèles expérimentaux in vitro et in vivo, qu'il réduit la mort neuronale. En appliquant une technique de microchirurgie pour induire une ischémie cérébrale transitoire chez la souris, nous avons montré que la thrombine peut stimuler les voies de signalisation intracellulaire médiées par MAPK et JNK par une approche moléculaire et l'analyse in vivo d'un inhibiteur spécifique de JNK (L JNK) .Nous avons également étudié l'impact de la thrombine sur la récupération fonctionnelle après une attaque et avons pu démontrer que ces mécanismes moléculaires peuvent améliorer la récupération motrice. La deuxième partie de cette étude des mécanismes de récupération après ischémie cérébrale est basée sur l'investigation des bases anatomiques de la plasticité des connections cérébrales, soit dans le modèle animal d'ischémie transitoire, soit chez l'homme. Selon des résultats précédemment publiés par divers groupes ,nous savons que des mécanismes de plasticité aboutissant à des degrés divers de récupération fonctionnelle sont mis enjeu après une lésion ischémique. Le résultat de cette réorganisation est une nouvelle architecture fonctionnelle et structurelle, qui varie individuellement selon l'anatomie de la lésion, l'âge du sujet et la chronicité de la lésion. Le succès de toute intervention thérapeutique dépendra donc de son interaction avec la nouvelle architecture anatomique. Pour cette raison, nous avons appliqué deux techniques de diffusion en résonance magnétique qui permettent de détecter les changements de microstructure cérébrale et de connexions anatomiques suite à une attaque : IRM par tenseur de diffusion (DT-IR1V) et IRM par spectre de diffusion (DSIRM). Grâce à la DT-IRM hautement sophistiquée, nous avons pu effectuer une étude de follow-up à long terme chez des souris ayant subi une ischémie cérébrale transitoire, qui a mis en évidence que les changements microstructurels dans l'infarctus ainsi que la modification des voies anatomiques sont corrélés à la récupération fonctionnelle. De plus, nous avons observé une réorganisation axonale dans des aires où l'on détecte une augmentation d'expression d'une protéine de plasticité exprimée dans le cône de croissance des axones (GAP-43). En appliquant la même technique, nous avons également effectué deux études, rétrospective et prospective, qui ont montré comment des paramètres obtenus avec DT-IRM peuvent monitorer la rapidité de récupération et mettre en évidence un changement structurel dans les voies impliquées dans les manifestations cliniques. Dans la dernière partie de ce travail, nous avons décrit la manière dont la DS-IRM peut être appliquée dans le domaine expérimental et clinique pour étudier la plasticité cérébrale après ischémie. Abstract Ischemic stroke is the third leading cause of death in developed countries and the disease responsible for the most serious long-term neurological disability. Understanding molecular and anatomical basis of stroke recovery is, therefore, extremely important and represents a major field of interest for basic and clinical research. Over the past 2 decades, much attention has focused on counteracting noxious effect of the ischemic insult with exogenous substances (oxygen radical scavengers, AMPA and NMDA receptor antagonists, MMP inhibitors etc) which were successfully tested in the experimental field -but which turned out to have controversial effects in clinical trials. A different but complementary approach to address ischemia pathophysiology and treatment options is to stimulate and investigate intrinsic mechanisms of neuroprotection using the "preconditioning effect": applying a brief insult protects against subsequent prolonged and detrimental ischemic episodes, by up-regulating powerful endogenous pathways that increase resistance to injury. We believe that this approach might offer an important insight into the molecular mechanisms responsible for endogenous neuroprotection. In addition, results from preconditioning model experiment may provide new strategies for making brain cells "naturally" more resistant to ischemic injury and accelerate their rate of functional recovery. In the first part of this work, we investigated down-stream mechanisms of neuroprotection induced by thrombin, a well known neuroprotectant which has been demonstrated to reduce stroke-induced cell death in vitro and in vivo experimental models. Using microsurgery to induce transient brain ischemia in mice, we showed that thrombin can stimulate both MAPK and JNK intracellular pathways through a molecular biology approach and an in vivo analysis of a specific kinase inhibitor (L JNK1). We also studied thrombin's impact on functional recovery demonstrating that these molecular mechanisms could enhance post-stroke motor outcome. The second part of this study is based on investigating the anatomical basis underlying connectivity remodeling, leading to functional improvement after stroke. To do this, we used both a mouse model of experimental ischemia and human subjects with stroke. It is known from previous data published in literature, that the brain adapts to damage in a way that attempts to preserve motor function. The result of this reorganization is a new functional and structural architecture, which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new architecture. For this reason, we applied diffusion magnetic resonance techniques able to detect micro-structural and connectivity changes following an ischemic lesion: diffusion tensor MRI (DT-MRI) and diffusion spectrum MRI (DS-MRI). Using DT-MRI, we performed along-term follow up study of stroke mice which showed how diffusion changes in the stroke region and fiber tract remodeling is correlating with stroke recovery. In addition, axonal reorganization is shown in areas of increased plasticity related protein expression (GAP 43, growth axonal cone related protein). Applying the same technique, we then performed a retrospective and a prospective study in humans demonstrating how specific DTI parameters could help to monitor the speed of recovery and show longitudinal changes in damaged tracts involved in clinical symptoms. Finally, in the last part of this study we showed how DS-MRI could be applied both to experimental and human stroke and which perspectives it can open to further investigate post stroke plasticity.

Predicting human resting-state functional connectivity from structural connectivity

In the cerebral cortex, the activity levels of neuronal populations are continuously fluctuating. When neuronal activity, as measured using functional MRI (fMRI), is temporally coherent across 2 populations, those populations are said to be functionally connected. Functional connectivity has previously been shown to correlate with structural (anatomical) connectivity patterns at an aggregate level. In the present study we investigate, with the aid of computational modeling, whether systems-level properties of functional networks-including their spatial statistics and their persistence across time-can be accounted for by properties of the underlying anatomical network. We measured resting state functional connectivity (using fMRI) and structural connectivity (using diffusion spectrum imaging tractography) in the same individuals at high resolution. Structural connectivity then provided the couplings for a model of macroscopic cortical dynamics. In both model and data, we observed (i) that strong functional connections commonly exist between regions with no direct structural connection, rendering the inference of structural connectivity from functional connectivity impractical; (ii) that indirect connections and interregional distance accounted for some of the variance in functional connectivity that was unexplained by direct structural connectivity; and (iii) that resting-state functional connectivity exhibits variability within and across both scanning sessions and model runs. These empirical and modeling results demonstrate that although resting state functional connectivity is variable and is frequently present between regions without direct structural linkage, its strength, persistence, and spatial statistics are nevertheless constrained by the large-scale anatomical structure of the human cerebral cortex.

External validation of the ASTRAL score to predict 3- and 12-month functional outcome in the China National Stroke Registry.

BACKGROUND AND PURPOSE: The ASTRAL score was recently introduced as a prognostic tool for acute ischemic stroke. It predicts 3-month outcome reliably in both the derivation and the validation European cohorts. We aimed to validate the ASTRAL score in a Chinese stroke population and moreover to explore its prognostic value to predict 12-month outcome. METHODS: We applied the ASTRAL score to acute ischemic stroke patients admitted to 132 study sites of the China National Stroke Registry. Unfavorable outcome was assessed as a modified Rankin Scale score >2 at 3 and 12 months. Areas under the curve were calculated to quantify the prognostic value. Calibration was assessed by comparing predicted and observed probability of unfavorable outcome using Pearson correlation coefficient. RESULTS: Among 3755 patients, 1473 (39.7%) had 3-month unfavorable outcome. Areas under the curve for 3 and 12 months were 0.82 and 0.81, respectively. There was high correlation between observed and expected probability of unfavorable 3- and 12-month outcome (Pearson correlation coefficient: 0.964 and 0.963, respectively). CONCLUSIONS: ASTRAL score is a reliable tool to predict unfavorable outcome at 3 and 12 months after acute ischemic stroke in the Chinese population. It is a useful tool that can be readily applied in clinical practice to risk-stratify acute stroke patients.