e-Repositori UPF :: Articles (Departament de Tecnologies de la Informació i les Comunicacions)

Enviaments recents

A porohyperelastic scheme targeted at high-performance computing frameworks for the simulation of the intervertebral disc
(Elsevier, 2025) Lialios, Dimitrios; Eguzkitza, Ane Betriz; Houzeaux, Guillaume; Casoni, Eva; Baumgartner, Laura; Noailly, Jérôme; Muñoz-Moya, Estefano; Gantenbein, Benjamin; Vázquez, Mariano
Background and Objective: The finite element method is widely used for studying the intervertebral disc at the organ level due to its ability to model complex geometries. An indispensable requirement for proper modelling of the intervertebral disc is a reliable porohyperelastic framework that captures the elaborate underlying mechanics. The increased complexity of such models requires significant computational power that is available within high-performance computing systems. The objective of this study is to present such a framework, validated both against literature and experiments, aiming to enable intervertebral disc research to benefit from state-of-the-art computational resources. Methods: In the context of this work, we implement a biphasic model that captures the mechanical response of the intricate, tissue-dependent models of the solid phase along with the hydrostatic pressure effects of the fluid phase. The tissue-dependent models involve the hyperelastic ground substance, fibrillar reinforcement, and osmotic swelling. The derived porohyperelastic, staggered scheme is implemented in Alya, a finite element code targeted at high-performance computing applications. The formulation is subsequently verified and validated by comparing the results of consolidation simulations with literature data for simulations and experiments using either generic or patient-specific geometries. Additionally, in-house experiments are replicated, evaluating the model’s ability to simulate alternating loading. Finally, the implementation’s circadian response is compared to previous implementation of similar material models in commercial software. Results: Results align well with experimental and literature findings in terms of disc height reduction (4% error), intradiscal pressure (14% error) and disc bulging. Validating the patient-specific geometry results in 4% and 7% deviation in measuring height loss. Simulations show excellent agreement with in-house experimental results, with less than 1% error regarding height reduction. Finally, the comparison to similar, published, earlier implementation in commercial software unveils excellent agreement of less than 1% error for the water content during circadian simulations. Simulation times are reported at 4 min per circadian cycle in the supercomputer Marenostrum V. Conclusions: This work presents a clear and validated formulation for simulating porohyperelastic materials based on assumptions that comply with the non-linear elasticity theory. The implementation in Alya enables intervertebral disc research to benefit from high-performance computing systems.
Parallel networks to predict TIMP and protease cell activity of nucleus pulposus cells exposed and not exposed to pro-inflammatory cytokines
(Wiley, 2025) Baumgartner, Laura; Witta, Sandra; Noailly, Jérôme
Background. Intervertebral disc (IVD) degeneration is characterized by a disruption of the balance between anabolic and catabolic cellular processes. Within the nucleus pulposus (NP), this involves increased levels of the pro-inflammatory cytokines interleukin 1beta (IL1B) and tumor necrosis factor (TNF) and an upregulation of the protease families matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). Primary inhibitors of these proteases are the tissue inhibitors of matrix metalloproteinases (TIMP). This work aims at contributing to a better understanding of the dynamics among proteases, TIMP, and pro-inflammatory cytokines within the complex, multifactorial environment of the NP. Methods. The Parallel Network (PN)-Methodology was used to estimate relative mRNA expressions of TIMP1–3, MMP3, and ADAMTS4 for five simulated human activities: walking, sitting, jogging, hiking with 20 kg extra weight, and exposure to high vibration. Simulations were executed for nutrient conditions in non- and early-degenerated IVD approximations. To estimate the impact of cytokines, the PN-Methodology inferred relative protein levels for IL1B and TNF, reintegrated as secondary stimuli into the network. Results. TIMP1 and TIMP2 expressions were found to be overall lower than TIMP3 expression. In the absence of pro-inflammatory cytokines, MMP3 and/or ADAMTS4 expressions were strongly downregulated in all conditions but vibration and hiking with extra weight. Pro-inflammatory cytokine exposure resulted in an impaired inhibition of MMP3, rather than of ADAMTS4, progressively rising with increasing nutrient deprivation. TNF mRNA was less expressed than IL1B. However, at the protein level, TNF was mainly responsible for the catabolic shift in the simulated pro-inflammatory environment. Overall, results agreed with previous experimental findings. Conclusions. The PN-Methodology successfully allowed the exploration of the relative dynamics of TIMP and protease regulations in different mechanical, nutritional, and inflammatory environments in the NP. It shall stand as a comprehensive tool to integrate in vitro model results in IVD research and approximate NP cell activities in complex multifactorial environments.
Ex vivo and in vitro proteomic approach to elucidate the relevance of IL-4 and IL-10 in intervertebral disc pathophysiology
(Wiley, 2025) Bermúdez-Lekerika, Paola; Tseranidou, Sofia; Kanelis, Exarchos; Nüesch, Andrea; Crump, Katherine B.; Alexopoulos, Leonidas G.; Wuertz-Kozak, Karin; Noailly, Jérôme; Le Maitre, Christine L.; Gantenbein, Benjamin
Background. This study investigates the native presence and potential anabolic effects of interleukin (IL)-4 and IL-10 in the human intervertebral disc (IVD). Methods. Human nucleus pulposus (NP) cells cultured in 3D from trauma and degenerate IVDs and NP explants were stimulated with 10 ng/mL IL-4, IL-10, or each in combination with 1 ng/mL IL-1β stimulation. The role of IL-4 and IL-10 in the IVD was evaluated using immunohistochemistry, gene expression, and Luminex multiplex immunoassay proteomics (73 secreted) and phosphoproteomics (21 phosphorylated proteins). Results. IL-4, IL-4R, and IL-10R expression and localization in human cartilage endplate tissue were demonstrated for the first time. No significant gene expression changes were noted under IL-4 or IL-10 stimulation. However, IL-1β stimulation significantly increased MMP3, COX2, TIMP1, and TRPV4 expression in NP cells from trauma IVDs. Combined IL-4 and IL-1β treatment induced a significant increase in protein secretion of IL-1α, IL-7, IL-16, IL-17F, IL-18, IFNγ, TNF, ST2, PROK1, bFGF2, and stem cell factor exclusively in NP cells from degenerated IVDs. Conversely, the secretome profile of explants revealed an IL-4–mediated decrease in CXCL13 following treatment with IL-1β. Combined IL-10 and IL-1β treatment increased neurotrophic growth factor secretion compared with IL-10 baseline. Conclusions. The NP cell phenotype affects the pleiotropic role of IL-4, which can induce a pro-inflammatory response in the presence of catabolic stimuli and enhance the effects of IL-1β in degenerated IVDs. Environmental factors, including 3D culture and hypoxia, may alter IL-4's role. Finally, IL-10's potential neurotrophic effects under catabolic stimuli warrant further investigation to clarify its role in IVD degeneration.
TNF induces catabolism in human cartilaginous endplate cells in 3D agarose culture under dynamic compression
(Nature Research, 2025) Crump, Katherine B.; Kanelis, Exarchos; Segarra-Queralt, Maria; Pascuet Fontanet, Andreu; Bermudez-Lekerika, Paola; Alminnawi, Ahmad; Geris, Liesbet; Alexopoulos, Leonidas G.; Noailly, Jérôme; Gantenbein, Benjamin
Intervertebral disc (IVD) degeneration is the leading cause of low back pain in young adults, and the cartilaginous endplate (CEP) is likely to play a key role in early IVD degeneration. To elucidate the effects of pro-inflammatory cytokines on the mechanobiology of the CEP, human CEP cells were seeded into 2% agarose, dynamically compressed up to 7%, and stimulated with tumor necrosis factor (TNF). It was hypothesized that dynamic compression would be sufficient to induce anabolism, while stimulation with TNF would induce catabolism. TNF was sufficient to induce a catabolic, time-dependent response in human CEP cells through downregulation of anabolic gene expression and increased secretion of pro-inflammatory proteins associated with herniated discs, bacteria inhibition, and pain. However, 7% strain or scaffold material, agarose, may not lead to full activation of integrins and downregulation of pro-inflammatory pathways, demonstrated in part through the unchanged gene expression of integrin subunits α5 and β1.
The role of sex, age, and BMI in treatment decisions for knee osteoarthritis: conservative management versus total knee replacement
(Springer, 2025) Ojeda Morillo, Fabiola Alejandra; Tío, Laura; Castro Domínguez, Francisco; Tassani, Simone; Noailly, Jérôme; Monfort, Jordi
Background. Knee osteoarthritis (KOA) has a complex, multifactorial nature with well-established risk factors which may influence treatment decisions. Here we want to identify distinctive characteristics between patients receiving conservative treatment versus total knee replacement (TKR), analyzing both patient-specific and knee-specific features. Methods. This case–control study compared patients assigned to TKR versus conservative management, examining subjects aged 60–75 years with radiographically confirmed KOA (Kellgren–Lawrence grades 2–3), with all participants evaluated by blinded clinicians using validated assessment tools including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Hospital Anxiety and Depression Scale (HADs), Pain Catastrophizing Scale (PCS) and Daily physical activity (DPA) questionnaires. The study employed multivariate analysis of variance for continuous variables at both patient and knee levels, followed by univariate analysis of variance for significant factors, while logistic and linear regression analyses were used to calculate odds ratios, with Bonferroni corrections applied to adjust p-values for multiple comparisons. Results. Between 2016 and 2020, the study included 87 patients (51 women and 36 men) with a mean age of 67.7 years in both treatment groups, with a slightly higher body mass index (BMI) of 31.9 kg/m2 in the TKR group vs 30.5 kg/m2 in the conservative management group. TKR patients demonstrated significantly worse scores in WOMAC, HADS, and PCS compared to the conservative management group, though DPA levels remained similar between both groups. At the knee level, women demonstrated significantly higher pain sensitivity and central sensitization compared to men, with no differences between conservative and TKR groups. Conclusions. Patients undergoing TKR exhibited significantly worse baseline clinical outcomes, particularly in WOMAC scores, despite having similar radiographic severity to those receiving conservative treatment, suggesting that functional and symptomatic measures may be more valuable than radiographic findings in determining surgical intervention.
Nucleus pulposus cell network modelling in the intervertebral disc
(Nature Research, 2025) Tseranidou, Sofia; Segarra-Queralt, Maria; Chemorion, Francis Kiptengwer; Le Maitre, Christine L.; Piñero González, Janet, 1977-; Noailly, Jérôme
Intervertebral disc degeneration (IDD) results from an imbalance between anabolic and catabolic processes in the extracellular matrix (ECM). Due to complex biochemical interactions, a comprehensive understanding is needed. This study presents a regulatory network model (RNM) for nucleus pulposus cells (NPC), representing normal intervertebral disc (IVD) conditions. The RNM includes 33 proteins, and 153 interactions based on literature, incorporating key NPC regulatory mechanisms. A semi-quantitative approach calculates the basal steady state, accurately reflecting normal NPC activity. Model validation through published studies replicated pro-catabolic and pro-anabolic shifts, emphasizing the roles of transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) in ECM regulation. This IVD RNM is a valuable tool for predicting IDD progression, offering insights into ECM degradation mechanisms and guiding experimental research on IVD health and degeneration.
A magnetic resonance image based atlas of the rabbit brain for automatic parcellation
(Public Library of Science (PLoS), 2013) Muñoz-Moreno, Emma; Arbat-Plana, Ariadna; Batalle, Dafnis; Soria Rodríguez, Guadalupe; Illa, Miriam; Prats-Galino, Alberto; Eixarch, Elisenda; Gratacós Solsona, Eduard
Rabbit brain has been used in several works for the analysis of neurodevelopment. However, there are not specific digital rabbit brain atlases that allow an automatic identification of brain regions, which is a crucial step for various neuroimage analyses, and, instead, manual delineation of areas of interest must be performed in order to evaluate a specific structure. For this reason, we propose an atlas of the rabbit brain based on magnetic resonance imaging, including both structural and diffusion weighted, that can be used for the automatic parcellation of the rabbit brain. Ten individual atlases, as well as an average template and probabilistic maps of the anatomical regions were built. In addition, an example of automatic segmentation based on this atlas is described.
Long-term functional outcomes and correlation with regional brain connectivity by MRI diffusion tractography metrics in a near-term rabbit model of intrauterine growth restriction
(Public Library of Science (PLoS), 2013) Illa, Miriam; Eixarch, Elisenda; Batalle, Dafnis; Arbat-Plana, Ariadna; Muñoz-Moreno, Emma; Figueras, Francesc; Gratacós Solsona, Eduard
Background. Intrauterine growth restriction (IUGR) affects 5–10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. Methodology. At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. Principal Findings. The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. Conclusions. The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis.
In vivo detection of perinatal brain metabolite changes in a rabbit model of intrauterine growth restriction (IUGR)
(Public Library of Science (PLoS), 2015) Simões, Rui Vasco; Muñoz-Moreno, Emma; Carbajo, Rodrigo J.; González-Tendero, Anna; Illa, Miriam; Sanz-Cortés, Magdalena; Pineda-Lucena, Antonio; Gratacós Solsona, Eduard
Background. Intrauterine growth restriction (IUGR) is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI) and spectroscopy (MRS), to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation. Methods. IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40–50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i) absolute metabolite quantifications, using linear fitting; (ii) local temperature estimations, based on the water chemical shift; and (iii) classification, using spectral pattern analysis. Results. Lower birth weight was associated with (i) smaller brain sizes, (ii) slightly lower brain temperatures, and (iii) differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA) in the cerebral cortex and hippocampus (suggesting neuronal impairment), and higher glycine levels in the striatum (possible marker of brain injury). Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum. Conclusions. IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin.
Structural brain network reorganization and social cognition related to adverse perinatal condition from infancy to early adolescence
(Frontiers, 2016) Muñoz-Moreno, Emma; Fischi-Gomez, Elda; Batalle, Dafnis; Borradori-Tolsa, Cristina; Eixarch, Elisenda; Thiran, Jean-Philippe; Gratacós Solsona, Eduard; Hüppi, Petra S.
Adverse conditions during fetal life have been associated to both structural and functional changes in neurodevelopment from the neonatal period to adolescence. In this study, connectomics was used to assess the evolution of brain networks from infancy to early adolescence. Brain network reorganization over time in subjects who had suffered adverse perinatal conditions is characterized and related to neurodevelopment and cognition. Three cohorts of prematurely born infants and children (between 28 and 35 weeks of gestational age), including individuals with a birth weight appropriated for gestational age and with intrauterine growth restriction (IUGR), were evaluated at 1, 6, and 10 years of age, respectively. A common developmental trajectory of brain networks was identified in both control and IUGR groups: network efficiencies of the fractional anisotropy (FA)-weighted and normalized connectomes increase with age, which can be related to maturation and myelination of fiber connections while the number of connections decreases, which can be associated to an axonal pruning process and reorganization. Comparing subjects with or without IUGR, a similar pattern of network differences between groups was observed in the three developmental stages, mainly characterized by IUGR group having reduced brain network efficiencies in binary and FA-weighted connectomes and increased efficiencies in the connectome normalized by its total connection strength (FA). Associations between brain networks and neurobehavioral impairments were also evaluated showing a relationship between different network metrics and specific social cognition-related scores, as well as a higher risk of inattention/hyperactivity and/or executive functional disorders in IUGR children.
Brain network characterization of high-risk preterm-born school-age children
(Elsevier, 2016) Fischi-Gomez, Elda; Muñoz-Moreno, Emma; Vasung, Lana; Griffa, Alessandra; Borradori-Tolsa, Cristina; Monnier, Maryline; Lazeyras, François; Thiran, Jean-Philippe; Hüppi, Petra S.
Higher risk for long-term cognitive and behavioral impairments is one of the hallmarks of extreme prematurity (EP) and pregnancy-associated fetal adverse conditions such as intrauterine growth restriction (IUGR). While neurodevelopmental delay and abnormal brain function occur in the absence of overt brain lesions, these conditions have been recently associated with changes in microstructural brain development. Recent imaging studies indicate changes in brain connectivity, in particular involving the white matter fibers belonging to the cortico-basal ganglia-thalamic loop. Furthermore, EP and IUGR have been related to altered brain network architecture in childhood, with reduced network global capacity, global efficiency and average nodal strength. In this study, we used a connectome analysis to characterize the structural brain networks of these children, with a special focus on their topological organization. On one hand, we confirm the reduced averaged network node degree and strength due to EP and IUGR. On the other, the decomposition of the brain networks in an optimal set of clusters remained substantially different among groups, talking in favor of a different network community structure. However, and despite the different community structure, the brain networks of these high-risk school-age children maintained the typical small-world, rich-club and modularity characteristics in all cases. Thus, our results suggest that brain reorganizes after EP and IUGR, prioritizing a tight modular structure, to maintain the small-world, rich-club and modularity characteristics. By themselves, both extreme prematurity and IUGR bear a similar risk for neurocognitive and behavioral impairment, and the here defined modular network alterations confirm similar structural changes both by IUGR and EP at school age compared to control. Interestingly, the combination of both conditions (IUGR + EP) does not result in a worse outcome. In such cases, the alteration in network topology appears mainly driven by the effect of extreme prematurity, suggesting that these brain network alterations present at school age have their origin in a common critical period, both for intrauterine and extrauterine adverse conditions.
Effects of orientation and anisometry of magnetic resonance imaging acquisitions on diffusion tensor imaging and structural connectomes
(Public Library of Science (PLoS), 2017) Tudela, Raúl; Muñoz-Moreno, Emma; López-Gil, Xavier; Soria Rodríguez, Guadalupe
Diffusion-weighted imaging (DWI) quantifies water molecule diffusion within tissues and is becoming an increasingly used technique. However, it is very challenging as correct quantification depends on many different factors, ranging from acquisition parameters to a long pipeline of image processing. In this work, we investigated the influence of voxel geometry on diffusion analysis, comparing different acquisition orientations as well as isometric and anisometric voxels. Diffusion-weighted images of one rat brain were acquired with four different voxel geometries (one isometric and three anisometric in different directions) and three different encoding orientations (coronal, axial and sagittal). Diffusion tensor scalar measurements, tractography and the brain structural connectome were analyzed for each of the 12 acquisitions. The acquisition direction with respect to the main magnetic field orientation affected the diffusion results. When the acquisition slice-encoding direction was not aligned with the main magnetic field, there were more artifacts and a lower signal-to-noise ratio that led to less anisotropic tensors (lower fractional anisotropic values), producing poorer quality results. The use of anisometric voxels generated statistically significant differences in the values of diffusion metrics in specific regions. It also elicited differences in tract reconstruction and in different graph metric values describing the brain networks. Our results highlight the importance of taking into account the geometric aspects of acquisitions, especially when comparing diffusion data acquired using different geometries.
Resting state networks in the TgF344-AD rat model of Alzheimer’s disease are altered from early stages
(Frontiers, 2019) Tudela, Raúl; Muñoz-Moreno, Emma; Sala-Llonch, Roser; López-Gil, Xavier; Soria Rodríguez, Guadalupe
A better and non-invasive characterization of the preclinical phases of Alzheimer’s disease (AD) is important to advance its diagnosis and obtain more effective benefits from potential treatments. The TgF344-AD rat model has been well characterized and shows molecular, behavioral and brain connectivity alterations that resemble the silent period of the pathology. Our aim was to longitudinally investigate functional brain connectivity in established resting-state networks (RSNs) obtained by independent component analysis (ICA) in a cohort of TgF344-AD and control rats every 3 months, from 5 to 18 months of age, to cover different stages of the disease. Before each acquisition, working memory performance was evaluated by the delayed non match-to-sample (DNMS) task. Differences in the temporal evolution were observed between groups in the amplitude and shape of the somatosensorial and sensorimotor networks but not in the whole default mode network (DMN). Subsequent high dimensional ICA analysis showed early alterations in the anterior DMN subnetwork activity of TgF344-AD rats compared to controls. Performance of DNMS task was positively correlated with somatosensorial network at 5 months of age in the wild-type (WT) animals but not in the Tg-F344 rats. At different time points, DMN showed negative correlation with cognitive performance in the control group while in the transgenic group the correlation was positive. In addition, behavioral differences observed at 5 months of age correlated with alterations in the posterior DMN subnetwork. We have demonstrated that functional connectivity using ICA represents a useful biomarker also in animal models of AD such as the TgF344AD rats, as it allows the identification of alterations associated with the progression of the disease, detecting differences in specific networks even at very early stages.
M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington’s disease
(eLife, 2020) Fernández-García, Sara; Conde-Berriozabal, Sara; García-García, Esther; Gort-Paniello, Clara; Bernal-Casas, David; García-Díaz Barriga, Gerardo; López-Gil, Xavier; Muñoz-Moreno, Emma; Soria Rodríguez, Guadalupe; Campa, Leticia; Artigas, Francesc; Rodríguez, Manuel José; Alberch, Jordi; Masana, Mercè
Huntington’s disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.
Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study
(Springer, 2021) Pascual-Antón, Raquel; Blasco-Serra, Arantxa; Muñoz-Moreno, Emma; Pilar-Cuéllar, Fuencisla; Garro-Martínez, Emilio; Florensa-Zanuy, Eva; López-Gil, Xavier; Campa, Víctor M.; Soria Rodríguez, Guadalupe; Adell, Albert
Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague–Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.
Spatio-temporal metabolic rewiring in the brain of TgF344-AD rat model of Alzheimer’s disease
(Nature Research, 2022) Muñoz-Moreno, Emma; Simões, Rui Vasco; Tudela, Raúl; López-Gil, Xavier; Soria Rodríguez, Guadalupe
Brain damage associated with Alzheimer's disease (AD) occurs even decades before the symptomatic onset, raising the need to investigate its progression from prodromal stages. In this context, animal models that progressively display AD pathological hallmarks (e.g. TgF344-AD) become crucial. Translational technologies, such as magnetic resonance spectroscopy (MRS), enable the longitudinal metabolic characterization of this disease. However, an integrative approach is required to unravel the complex metabolic changes underlying AD progression, from early to advanced stages. TgF344-AD and wild-type (WT) rats were studied in vivo on a 7 Tesla MRI scanner, for longitudinal quantitative assessment of brain metabolic profile changes using MRS. Disease progression was investigated at 4 time points, from 9 to 18 months of age, and in 4 regions: cortex, hippocampus, striatum, and thalamus. Compared to WT, TgF344-AD rats replicated common findings in AD patients, including decreased N-acetylaspartate in the cortex, hippocampus and thalamus, and decreased glutamate in the thalamus and striatum. Different longitudinal evolution of metabolic concentration was observed between TgF344-AD and WT groups. Namely, age-dependent trajectories differed between groups for creatine in the cortex and thalamus and for taurine in cortex, with significant decreases in Tg344-AD animals; whereas myo-inositol in the thalamus and striatum showed greater increase along time in the WT group. Additional analysis revealed divergent intra- and inter-regional metabolic coupling in each group. Thus, in cortex, strong couplings of N-acetylaspartate and creatine with myo-inositol in WT, but with taurine in TgF344-AD rats were observed; whereas in the hippocampus, myo-inositol, taurine and choline compounds levels were highly correlated in WT but not in TgF344-AD animals. Furthermore, specific cortex-hippocampus-striatum metabolic crosstalks were found for taurine levels in the WT group but for myo-inositol levels in the TgF344-AD rats. With a systems biology perspective of metabolic changes in AD pathology, our results shed light into the complex spatio-temporal metabolic rewiring in this disease, reported here for the first time. Age- and tissue-dependent imbalances between myo-inositol, taurine and other metabolites, such as creatine, unveil their role in disease progression, while pointing to the inadequacy of the latter as an internal reference for quantification.
Intense long-term training impairs brain health compared with moderate exercise: experimental evidence and mechanisms
(Wiley, 2022) Sangüesa, Gemma; Batlle, Montserrat; Muñoz-Moreno, Emma; Soria Rodríguez, Guadalupe; Alcarraz, Anna; Rubies, Cira; Sitjà-Roqueta, Laia; Solana, Elisabeth; Martínez-Heras, Eloy; Meza-Ramos, Aline; Amaro, Sergio; Llufriu, Sara; Mont, Lluís; Guasch, Eduard
The consequences of extremely intense long-term exercise for brain health remain unknown. We studied the effects of strenuous exercise on brain structure and function, its dose‒response relationship, and mechanisms in a rat model of endurance training. Five-week-old male Wistar rats were assigned to moderate (MOD) or intense (INT) exercise or a sedentary (SED) group for 16 weeks. MOD rats showed the highest motivation and learning capacity in operant conditioning experiments; SED and INT presented similar results. In vivo MRI demonstrated enhanced global and regional connectivity efficiency and clustering as well as a higher cerebral blood flow (CBF) in MOD but not INT rats compared with SED. In the cortex, downregulation of oxidative phosphorylation complex IV and AMPK activation denoted mitochondrial dysfunction in INT rats. An imbalance in cortical antioxidant capacity was found between MOD and INT rats. The MOD group showed the lowest hippocampal brain-derived neurotrophic factor levels. The mRNA and protein levels of inflammatory markers were similar in all groups. In conclusion, strenuous long-term exercise yields a lesser improvement in learning ability than moderate exercise. Blunting of MOD-induced improvements in CBF and connectivity efficiency, accompanied by impaired mitochondrial energetics and, possibly, transient local oxidative stress, may underlie the findings in intensively trained rats.
Clinical relevance of different loads of perivascular spaces according to their localization in patients with a recent small subcortical infarct
(MDPI, 2024) Sozzi, Caterina; Brenlla, Carla; Bartolomé, Inés; Girona, Andrés; Muñoz-Moreno, Emma; Laredo, Carlos; Rodríguez-Vázquez, Alejandro; Doncel-Moriano, Antonio; Rudilosso, Salvatore; Chamorro, Ángel
Background and Purpose: Perivascular spaces (PVS) are usually enlarged in small vessel disease (SVD). However, the significance of PVS patterns in different locations is uncertain. Hence, we analyzed the distribution of PVS in patients with a recent small subcortical infarct (RSSI) and their correlation with clinical and imaging factors. Materials and Methods: In a cohort of 71 patients with an RSSI with complete clinical data, including the Pittsburgh Sleep Quality Index (PSQI), we segmented PVS in white matter (WM-PVS), basal ganglia (BG-PVS), and brainstems (BS-PVS) on 3T-MRI T2-weighted sequences, obtaining fractional volumes (%), and calculated the WM/BG-PVS ratio. We analyzed the Pearson’s correlation coefficients between PVS regional loads. We used normalized PVS measures to assess the associations with clinical and MRI-SVD features (white matter hyperintensities (WMHs), number of lacunes, and microbleeds) in univariable and multivariable linear regressions adjusted for age, sex, and hypertension. Results: In our cohort (mean age 70 years; 27% female), the Pearson’s correlation coefficients between WM-PVS/BG-PVS, WM-PVS/BS-PVS, and BG-PVS/BS-PVS were 0.67, 0.61, and 0.59 (all p < 0.001). In the adjusted models, BG-PVS were associated with lacunes (p = 0.034), WMHs (p = 0.006), and microbleeds (p = 0.017); WM-PVS with lacunes (p = 0.003); while BS-PVS showed no associations. The WM/BG-PVS ratio was associated with lacunes (p = 0.018) and the PSQI (p = 0.046). Conclusions: PVS burdens in different regions are highly correlated in patients with RSSI but with different SVD patterns. Sleep quality impairment might affect waste removal mechanisms differently in the WM and BG regions.
Locus coeruleus integrity and neuropsychiatric symptoms in a cohort of early- and late-onset Alzheimer's disease
(Wiley, 2024) Falgas, Neus; Peña-González, Marta; Guillén, Núria; Morales-Ruiz, Manuel; Sánchez Valle, Raquel
Introduction. Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage. Methods. One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations. Results. EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers. Discussion. Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD. Highlights. LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.
Defective thyroid hormone transport to the brain leads to astroglial alterations
(Elsevier, 2024) Guillén-Yunta, Marina; García-Aldea, Ángel; Valcárcel-Hernández, Víctor; Sanz-Bógalo, Ainara; Muñoz-Moreno, Emma; Matheus, Maria Gisele; Grijota-Martínez, Carmen; Montero-Pedrazuela, Ana; Guadaño-Ferraz, Ana; Bárez-López, Soledad
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

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