Regional hippocampal vulnerability in early multiple sclerosis: a dynamic pathological spreading from dentate gyrus to CA1

"This is the peer reviewed version of the following article: Planche, V., Koubiyr, I., Romero, J. E., Manjon, J. V., Coupé, P., Deloire, M., ... & Tourdias, T. (2018). Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA 1. Human brain mapping, 39(4), 1814-1824., which has been published in final form at https://doi.org/10.1002/hbm.23970. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] Background: Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate. Method: We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques. Results: At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R-2 = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (beta = 0.87, p < .05). Conclusion: The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance.ARSEP Foundation; Bordeaux University Hospital; TEVA Laboratories; French Agence Nationale de la Recherche, Grant/Award Numbers: ANR-10-LABX-57, ANR-10-LABX-43, ANR-10-IDEX-03-02, ANR-10-COHO-002; UPV, Grant/Award Numbers: UPV2016-0099, TIN2013-43457-R; Ministerio de Economia y competitividadPlanche, V.; Koubiyr, I.; Romero Gómez, JE.; Manjón Herrera, JV.; Coupe, P.; Deloire, M.; Dousset, V.... (2018). Regional hippocampal vulnerability in early multiple sclerosis: a dynamic pathological spreading from dentate gyrus to CA1. Human Brain Mapping. 39(4):1814-1824. https://doi.org/10.1002/hbm.23970S18141824394Avants, B. B., Tustison, N. J., Song, G., Cook, P. A., Klein, A., & Gee, J. C. (2011). A reproducible evaluation of ANTs similarity metric performance in brain image registration. NeuroImage, 54(3), 2033-2044. doi:10.1016/j.neuroimage.2010.09.025Bakker, A., Kirwan, C. B., Miller, M., & Stark, C. E. L. (2008). Pattern Separation in the Human Hippocampal CA3 and Dentate Gyrus. Science, 319(5870), 1640-1642. doi:10.1126/science.1152882Coupé, P., Manjón, J. V., Chamberland, M., Descoteaux, M., & Hiba, B. (2013). Collaborative patch-based super-resolution for diffusion-weighted images. NeuroImage, 83, 245-261. doi:10.1016/j.neuroimage.2013.06.030De Stefano, N., Airas, L., Grigoriadis, N., Mattle, H. P., O’Riordan, J., Oreja-Guevara, C., … Kieseier, B. C. (2014). Clinical Relevance of Brain Volume Measures in Multiple Sclerosis. CNS Drugs, 28(2), 147-156. doi:10.1007/s40263-014-0140-zDu, A. 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Multiple Sclerosis Journal, 23(9), 1214-1224. doi:10.1177/1352458516675750Planche, V., Panatier, A., Hiba, B., Ducourneau, E.-G., Raffard, G., Dubourdieu, N., … Tourdias, T. (2017). Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis. Brain, Behavior, and Immunity, 60, 240-254. doi:10.1016/j.bbi.2016.11.010Planche, V., Ruet, A., Charré-Morin, J., Deloire, M., Brochet, B., & Tourdias, T. (2017). Pattern separation performance is decreased in patients with early multiple sclerosis. Brain and Behavior, 7(8), e00739. doi:10.1002/brb3.739Polman, C. H., Reingold, S. C., Banwell, B., Clanet, M., Cohen, J. A., Filippi, M., … Wolinsky, J. S. (2011). Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of Neurology, 69(2), 292-302. doi:10.1002/ana.22366Rocca, M. A., Longoni, G., Pagani, E., Boffa, G., Colombo, B., Rodegher, M., … Filippi, M. (2015). 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Réorganisation des réseaux cérébraux dans les stades précoces de la sclérose en plaques

Cognitive impairment is frequent in multiple sclerosis (MS) but its underlying mechanisms are still poorly understood. MRI techniques have been a valuable tool to investigate the biological substrates of cognitive processes. The objective of this thesis was to better understand the pathophysiological mechanisms of cognitive functioning at the early stage of MS. We followed clinically isolated syndrome (CIS) patients for one year, using neuropsychological tests, conventional and more advanced MRI techniques. We first demonstrated a differential gray matter vulnerability at the beginning of MS with a pathological spread from the hippocampus towards the cortex. We showed that the first microstructural alterations taking place within the hippocampus were able to predict its future volume loss. After that, we were interested in the potential brain functional reorganization at this stage of the disease. Using resting-state functional MRI, we were able to demonstrate very early regional brain functional reorganization starting from the disease onset and becoming more pronounced after one year of evolution. We also noticed a preservation of cognitive performances in CIS patients, which we found was associated to more functional reorganization. These results suggested then a compensation mechanism at the first year after a CIS. However, the relationship between these functional changes and the underlying anatomy was still missing. Thus, we combined resting-state functional MRI and diffusion tensor imaging to represent both functional and structural connectivity. Using the structural-functional coupling parameter, representing the association between structural and functional connections, we showed a decoupling one year after the disease onset in three major networks (salience, visual and somatomotor networks). This decoupling was noticed while cognitive performances were preserved and functional reorganization present. These last results led us to suggest that the functional reorganization at this stage, acting as a compensation mechanism, occurs along indirect anatomical pathways. In order to confirm these results and further follow-up brain networks topology and its impact on cognition, we are currently calling back our CIS patients for their 5-year visit.Les troubles cognitifs sont fréquents dans la sclérose en plaques (SEP) mais leurs mécanismes sous-jacents sont encore mal connus. Les techniques d’IRM ont été indispensables pour essayer de mieux comprendre les substrats biologiques des processus cognitifs. L’objectif de cette thèse est de mieux comprendre les mécanismes physiopathologiques du fonctionnement cognitif dans les stades précoces de la SEP. Pour cela, nous avons étudié une cohorte de patients atteints de syndrome cliniquement isolé (SCI) pendant un an, en réalisant une batterie de tests neuropsychologiques ainsi qu’un examen IRM. Nous avons tout d’abord démontré une atteinte précoce de la substance grise, en particulier au niveau de l’hippocampe, se propageant vers le cortex après un an d’évolution. L’atteinte microstructurale précoce de l’hippocampe était capable de prédire sa perte de volume. Ensuite, nous nous sommes intéressés à la réorganisation des réseaux cérébraux fonctionnels à ce stade précoce de la maladie. En utilisant l’IRM fonctionnelle de repos, nous avons démontré une réorganisation cérébrale fonctionnelle précoce impliquant plusieurs régions cérébrales. Cette réorganisation était encore plus prononcée après un an d’évolution. Au même moment, nos patients présentaient un fonctionnement cognitif normal qui était associé au niveau de réorganisation cérébrale présente. Ces résultats suggèrent un mécanisme de compensation aux stades précoces de la pathologie. La relation entre ces modifications fonctionnelles et l’anatomie sous-jacente est inconnue dans la SEP. Nous avons ainsi décidé de combiner l’IRM fonctionnelle de repos et l’imagerie par tenseurs de diffusion pour étudier à la fois la connectivité fonctionnelle et la connectivité structurelle. En utilisant le paramètre de couplage structurel-fonctionnel, nous avons démontré un découplage, un an après l’apparition de la maladie, au niveau de trois réseaux cérébraux du repos (salience, visuel et somato-moteur). Ce découplage était observé alors même que les performances cognitives de nos patients étaient préservées et que la réorganisation fonctionnelle était présente. Ces résultats suggèrent que cette réorganisation fonctionnelle à ce stade, agissant comme un mécanisme de compensation, se produit à travers des connections anatomiques indirectes. Afin de confirmer ces résultats et de suivre l’évolution des réseaux cérébraux et leur impact sur la cognition, nous avons recontacté nos patients SCI pour un suivi à 5 ans

The reorganization of human brain networks in the early stages of multiple sclerosis

Les troubles cognitifs sont fréquents dans la sclérose en plaques (SEP) mais leurs mécanismes sous-jacents sont encore mal connus. Les techniques d’IRM ont été indispensables pour essayer de mieux comprendre les substrats biologiques des processus cognitifs. L’objectif de cette thèse est de mieux comprendre les mécanismes physiopathologiques du fonctionnement cognitif dans les stades précoces de la SEP. Pour cela, nous avons étudié une cohorte de patients atteints de syndrome cliniquement isolé (SCI) pendant un an, en réalisant une batterie de tests neuropsychologiques ainsi qu’un examen IRM. Nous avons tout d’abord démontré une atteinte précoce de la substance grise, en particulier au niveau de l’hippocampe, se propageant vers le cortex après un an d’évolution. L’atteinte microstructurale précoce de l’hippocampe était capable de prédire sa perte de volume. Ensuite, nous nous sommes intéressés à la réorganisation des réseaux cérébraux fonctionnels à ce stade précoce de la maladie. En utilisant l’IRM fonctionnelle de repos, nous avons démontré une réorganisation cérébrale fonctionnelle précoce impliquant plusieurs régions cérébrales. Cette réorganisation était encore plus prononcée après un an d’évolution. Au même moment, nos patients présentaient un fonctionnement cognitif normal qui était associé au niveau de réorganisation cérébrale présente. Ces résultats suggèrent un mécanisme de compensation aux stades précoces de la pathologie. La relation entre ces modifications fonctionnelles et l’anatomie sous-jacente est inconnue dans la SEP. Nous avons ainsi décidé de combiner l’IRM fonctionnelle de repos et l’imagerie par tenseurs de diffusion pour étudier à la fois la connectivité fonctionnelle et la connectivité structurelle. En utilisant le paramètre de couplage structurel-fonctionnel, nous avons démontré un découplage, un an après l’apparition de la maladie, au niveau de trois réseaux cérébraux du repos (salience, visuel et somato-moteur). Ce découplage était observé alors même que les performances cognitives de nos patients étaient préservées et que la réorganisation fonctionnelle était présente. Ces résultats suggèrent que cette réorganisation fonctionnelle à ce stade, agissant comme un mécanisme de compensation, se produit à travers des connections anatomiques indirectes. Afin de confirmer ces résultats et de suivre l’évolution des réseaux cérébraux et leur impact sur la cognition, nous avons recontacté nos patients SCI pour un suivi à 5 ans.Cognitive impairment is frequent in multiple sclerosis (MS) but its underlying mechanisms are still poorly understood. MRI techniques have been a valuable tool to investigate the biological substrates of cognitive processes. The objective of this thesis was to better understand the pathophysiological mechanisms of cognitive functioning at the early stage of MS. We followed clinically isolated syndrome (CIS) patients for one year, using neuropsychological tests, conventional and more advanced MRI techniques. We first demonstrated a differential gray matter vulnerability at the beginning of MS with a pathological spread from the hippocampus towards the cortex. We showed that the first microstructural alterations taking place within the hippocampus were able to predict its future volume loss. After that, we were interested in the potential brain functional reorganization at this stage of the disease. Using resting-state functional MRI, we were able to demonstrate very early regional brain functional reorganization starting from the disease onset and becoming more pronounced after one year of evolution. We also noticed a preservation of cognitive performances in CIS patients, which we found was associated to more functional reorganization. These results suggested then a compensation mechanism at the first year after a CIS. However, the relationship between these functional changes and the underlying anatomy was still missing. Thus, we combined resting-state functional MRI and diffusion tensor imaging to represent both functional and structural connectivity. Using the structural-functional coupling parameter, representing the association between structural and functional connections, we showed a decoupling one year after the disease onset in three major networks (salience, visual and somatomotor networks). This decoupling was noticed while cognitive performances were preserved and functional reorganization present. These last results led us to suggest that the functional reorganization at this stage, acting as a compensation mechanism, occurs along indirect anatomical pathways. In order to confirm these results and further follow-up brain networks topology and its impact on cognition, we are currently calling back our CIS patients for their 5-year visit

Mult Scler

Background: The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. Objective: This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. Methods: Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural–functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure–function relationships. Results: Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural–functional coupling had increased significantly after 5 years. This structural–functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. Conclusion: Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability

Altered functional brain states predict cognitive decline 5 years after a clinically isolated syndrome

© The Author(s), 2022.Background: Cognitive impairment occurs in the earliest stages of multiple sclerosis (MS) together with altered functional connectivity (FC). Objective: The aim of this study was to investigate the evolution of dynamic FC states in early MS and their role in shaping cognitive decline. Methods: Overall, 32 patients were enrolled after their first neurological episode suggestive of MS and underwent cognitive evaluation and resting-state functional MRI (fMRI) over 5 years. In addition, 28 healthy controls were included at baseline. Results: Cognitive performance was stable during the first year and declined after 5 years. At baseline, the number of transitions between states was lower in MS compared to controls (p = 0.01). Over time, frequency of high FC states decreased in patients (p = 0.047) and increased in state with low FC (p = 0.035). Cognitive performance at Year 5 was best predicted by the mean connectivity of high FC state at Year 1. Conclusion: Patients with early MS showed reduced functional network dynamics at baseline. Longitudinal changes showed longer time spent in a state of low FC but less time spent and more connectivity disturbance in more integrative states with high within- and between-network FC. Disturbed FC within this more integrative state was predictive of future cognitive decline

Front Neurol

While memory impairment in multiple sclerosis (MS) is known to be associated with hippocampal alterations, whether hippocampal networks could dynamically reorganize as a compensation mechanism is still a matter of debate. In this context, our aim was to identify the patterns of structural and functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances in early MS. Thirty-two patients with a first episode suggestive of MS together with 10 matched healthy controls were prospectively explored at baseline, 1 and 5 years follow up. They were scanned with MRI and underwent a neuropsychological battery of tests that included the Selective Reminding Test and the Brief Visual Memory Test Revised to assess verbal and visuo-spatial memory, respectively. Hippocampal volume was computed together with four graph theory metrics to study the structural and functional connectivity of both hippocampi with the rest of the brain. Associations between network parameters and memory performances were assessed using linear mixed-effects (LME) models. Considering cognitive abilities, verbal memory performances of patients decreased over time while visuo-spatial memory performances were maintained. In parallel, hippocampal volumes decreased significantly while structural and functional connectivity metrics were modified, with an increase in hippocampal connections over time. More precisely, these modifications were indicating a reinforcement of hippocampal short-distance connections. LME models revealed that the drop in verbal memory performances was associated with hippocampal volume loss, while the preservation of visuo-spatial memory performances was linked to decreased hippocampal functional shortest path length. In conclusion, we demonstrated a differential impairment in memory performances in the early stages of MS and an important interplay between hippocampal-related structural and functional networks and those performances. As the structural damage increases, functional reorganization seems to be able to maintain visuo-spatial memory performances with strengthened short-distance connections.Translational Research and Advanced Imaging Laborator

Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome

International audienc

J Neurosci Res

Theory of mind (ToM) seems to be affected in multiple sclerosis (MS). MRI studies suggested a role of the amygdala in social cognitive performances. Therefore, we explored the role of the amygdala network in ToM using a multimodal MRI approach. In MS, patients with impaired ToM showed contradictory dysexecutive neuropsychological profile. Therefore, we compared neural networks involved in ToM and executive functions (EFs). Twenty patients with relapsing-remitting MS and 15 matched healthy controls were selected. ToM (Faux Pas test and mind stories) and EFs were assessed within and outside the scanner. All subjects underwent a battery of neuropsychological tests. Multimodal MRI with structural (diffusion imaging) and functional (resting-state and task-based) sequences was used to analyze the role and connections of the amygdala in ToM functioning. Cognitive and ToM performances were similar between patients and controls. Resting-state data revealed decreased connectivity of the left amygdala with frontal areas in patients compared to controls (p < 0.0001). During the task-based functional MRI, patients demonstrated increased connectivity between the amygdala and several cerebellar and left temporal regions (all p < 0.05). The microstructural alterations between the left amygdala and left temporal regions were associated with increased functional connectivity within the same pathway (r = 0.74; p < 0.01). No overlap was observed between functional networks involved in ToM and EFs. Our study demonstrates more connectivity recruitment between the amygdala and cerebellar and temporal regions in MS patients to reach preserved ToM performance. Microstructural abnormalities have been related to this compensatory network. Finally, different networks were involved in EFs and ToM. © 2021 Wiley Periodicals LLC.Observatoire Français de la Sclérose en Plaque

Longitudinal study of functional brain network reorganization in clinically isolated syndrome

International audienceBackground:There is a lack of longitudinal studies exploring the topological organization of functional brain networks at the early stages of multiple sclerosis (MS).Objective:This study aims to assess potential brain functional reorganization at rest in patients with CIS (PwCIS) after 1 year of evolution and to characterize the dynamics of functional brain networks at the early stage of the disease.Methods:We prospectively included 41 PwCIS and 19 matched healthy controls (HCs). They were scanned at baseline and after 1 year. Using graph theory, topological metrics were calculated for each region. Hub disruption index was computed for each metric.Results:Hub disruption indexes of degree and betweenness centrality were negative at baseline in patients (p < 0.05), suggesting brain reorganization. After 1 year, hub disruption indexes for degree and betweenness centrality were still negative (p < 0.00001), but such reorganization appeared more pronounced than at baseline. Different brain regions were driving these alterations. No global efficiency differences were observed between PwCIS and HCs either at baseline or at 1 year.Conclusion:Dynamic changes in functional brain networks appear at the early stages of MS and are associated with the maintenance of normal global efficiency in the brain, suggesting a compensatory effect