Articles publicats en revistes (Institut de Neurociències (UBNeuro))

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Perceptual representations mediate effects of stimulus properties on liking for music
(New York Academy of Sciences., 2024-02-06) Clemente, Ana; Kaplan, Thomas M.; Pearce, Marcus, T.
Perceptual pleasure and its concomitant hedonic value play an essential role in every- day life, motivating behavior and thus influencing how individuals choose to spend their time and resources. However, how pleasure arises from perception of sensory infor- mation remains relatively poorly understood. In particular, research has neglected the question of how perceptual representations mediate the relationships between stimu- lus properties and liking (e.g., stimulus symmetry can only affect liking if it is perceived). The present research addresses this gap for the first time, analyzing perceptual and liking ratings of 96 nonmusicians (power of 0.99) and finding that perceptual represen- tations mediate effects of feature-based and information-based stimulus properties on liking for a novel set of melodies varying in balance, contour, symmetry, or complex- ity. Moreover, variability due to individual differences and stimuli accounts for most of the variance in liking. These results have broad implications for psychological research on sensory valuation, advocating a more explicit account of random variability and the mediating role of perceptual representations of stimulus properties.
Neuroaxonal Injury May Mediate the Association Between Hyperglycemia and Prognosis in Spontaneous Subarachnoid Hemorrhage
(Humana Press., 2025-02-01) Santana Moreno, Daniel; Llull Estrany, Laura; Mosteiro Cadaval, Alejandra; Pedrosa Eguílez, Leire; Pujol Fontrodona, Gabriel; Zattera, Luigi; Werner, Mariano; Martín, Abraham; Justicia Mercader, Carles; Chamorro, Ángel; Torné, Ramón; Amaro Delgado, Sergio
Hyperglycemia during early brain injury (EBI) period after spontaneous subarachnoid hemorrhage (SAH) is associated with poor outcome, but the underlying physiopathology is unknown. This study assessed if hyperglycemia during EBI is associated with markers of neuroaxonal injury and whether these biomarkers partially account for the association between hyperglycemia and poor clinical outcome. Ninety-two SAH patients admitted within 24 h of bleeding onset were prospectively included. Glucose levels were measured at arrival and every 6 h for 72 h. Serum neurofilament light chain (NFL) levels were measured at 72 h. Functional outcome was assessed with the modified Rankin Scale (mRS) at 90 days (poor outcome, mRS > 2). The association between glucose metrics, NFL levels, and clinical outcome was assessed with univariate and multivariate analyses. Mediation analysis was performed to examine the potential chain in which NFL may mediate the relationship between glucose and functional outcome. Higher glucose and NFL levels during EBI were associated with poor clinical outcome in adjusted analysis. NFL levels were associated with older age, higher initial severity, and higher glucose levels during EBI period. In adjusted mediation analyses, the association between glucose and clinical outcome was significantly mediated by NFL levels. The mediator NFL explained 25% of the association between glucose during EBI period and poor functional outcome at 90 days. In SAH, the association between glucose levels during EBI and poor clinical outcome might be significantly mediated by NFL levels. The link between hyperglycemia and poor clinical outcome might be explained in part through secondary neuroaxonal injury.
Reservoir computing in simulated neuronal cultures: Effectof network structure
(American Institute of Physics (AIP), 2026-02-17) Mats Houben, Akke; Haeb, Anna-Christina; García Ojalvo, Jordi; Soriano i Fradera, Jordi
Biological neurons are emerging as attractive candidates for artificial intelligence and machine learning applications given their natural energy efficiency and self-repair capacity. However, they differ from their idealized artificial counterparts. Biological neurons have highly variable and noisy dynamics and display intrinsic spontaneous activity instead of purely input-driven dynamics. Moreover, biological neuronal networks have physically constrained and highly plastic connections, leading to a complex and ever evolving connectivity structure. Here, we investigate (numerically and with preliminary experimental data) the stability of the input responses of neuronal cultures using a reservoir computing framework. Utilizing a numerical model for the growth and activity of neuronal cultures, previously used to model experimental data, we investigate the effect of large-scale network topology, specifically homogeneous vs modular architectures, on fading memory, reservoir performance under increasingly noisy dynamics, and robustness to network rewiring. We find that modular networks exhibit longer fading memory time, sustain higher performance under noisy conditions, and are more robust to connectivity rewiring than homogeneous networks. Finally, we observe no relationship between some characteristics of the network adjacency matrix (specifically its spectral properties) and reservoir computing performance.
Social interaction shapes and boosts second language learning: virtual reality can show us how
(Springer Science and Business Media LLC, 2025-12-19) Zappa, Ana; Slater, Mel; Rodríguez Fornells, Antoni
Social interaction can play a crucial role in how a second language (L2) is learned. In the current review, we examine theoretical frameworks and empirical studies demonstrating how social factors influence L2 learning, but we also identify gaps in the current literature. We propose using virtual reality (VR) as a methodology to fill these gaps with controlled, ecologically valid social simulations that can elucidate how social factors shape L2 learning.
Adult-specific Reelin expression alters striatal neuronal organization. Implications for neuropsychiatric disorders.
(Frontiers Media, 2022-02-22) Pardo Muñoz, Mónica; Gregorio Jordán, Sara; Montalban, Enrica; Pujadas Puigdomènech, Lluís; Elias-Tersa, Alba; Vílchez Acosta, Alba del Valle; Parent, Annabelle; Auladell i Costa, M.Carme; Girault, Jean-Antoine; Vila, Miquel; Angus, C. Nairn; Manso Sanz, Yasmina; Soriano Garcia, Eduardo
In addition to neuronal migration, brain development, and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. Moreover, heterozygous reeler mice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brain striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by μ-opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal parvalbumin- and cholinergic-interneurons, and to a slight increase in tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.
Polygenic risk scores mediating functioning outcomes through cognitive and clinical features in youth at family risk and controls
(Elsevier B.V., 2024-04) Gonzàlez Segura, Àlex; Serna, Elena de la, 1978-; Sugranyes Ernest, Gisela; Baeza, Inmaculada, 1970-; Valli, Isabel; Martínez Serrano, Irene; Díaz Caneja, Covadonga M.; Andreu-Bernabeu, Álvaro; Moreno, Dolores; Gassó Astorga, Patricia; Rodríguez Ferret, Natalia ; Martínez Pinteño, Albert; Prohens Coll, Llucia; Torrent Font, Carla; García Rizo, Clemente; Mas Herrero, Sergi; Castro Fornieles, Josefina
Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions.
Neural encoding of speech-in-noise in neonates: A frequency-following response study
(Acoustical Society of America, 2025-09-01) Mondéjar-Segovia, Alejandro; Gorina-Careta, Natàlia; Arenillas-Alcón, Sonia; Koravand, Amineh; Costa Faidella, Jordi; Ribas-Prats, Teresa; Gómez Roig, Ma. Dolores; Escera i Micó, Carles
Background noise disrupts the neural encoding of speech, making it particularly challenging to extract a speaker's voice from competing voices-an ability crucial for successful speech processing and communication. This disruption occurs across all ages, with infants and older adults being particularly vulnerable. In infancy, when robust speech encoding is fundamental for native language acquisition, the presence of background noise could have significant consequences for the development of speech and language processing. This study investigates the impact of background noise on the neural encoding of speech sounds in neonates. We recorded the frequency-following response to a /da/ syllable in both quiet and noise conditions from 25 healthy-term neonates and 21 normal-hearing adults. Results revealed higher neural responses in the adult group compared to newborns. Both groups exhibited reduced spectral amplitudes in the noise condition, with adults showing a greater decrease in the fundamental frequency spectral amplitude during the consonant transition compared to the steady vowel section. In contrast, neonates displayed similar disruption across both sections, possibly reflecting their immature auditory systems and limited exposure to higher-frequency formants in utero. This study represents a first step toward understanding the development of speech-in-noise processing from birth.
Current perspectives on psychedelic treatments in Europe
(Elsevier Ltd., 2026-02-01) Madero Gómez, Santiago; Soto Angona, Oscar; Ona, Genis; Sánchez-Moreno, José; Vieta i Pascual, Eduard, 1963-
In this viewpoint, we explore the evolving landscape of psychedelic-assisted therapy in Europe, focusing on clinical, regulatory, and therapeutic developments. While access remains limited, recent initiatives in Switzerland, Germany, and the Czech Republic illustrate growing momentum toward regulated use. We examine the debate surrounding psychedelics as pharmacological agents versus psychotherapeutic catalysts and argue for an integrative framework that considers neurobiological mechanisms, subjective experience, and contextual factors. We focus on how their effects, particularly those involving neuroplasticity and critical periods, may interact with psychotherapeutic processes. We highlight the importance of context and psychological support in shaping outcomes and discuss the challenges of implementing scalable care models. Regulatory fragmentation and methodological complexities continue to hinder progress, but publicly funded trials such as EPIsoDE and PsyPal offer promising examples of ethical and effective approaches. In our view, the future of psychedelic therapy lies not in simplifying its complexity, but in embracing it.
Human microglia-like cells differentiated from monocytes with GM-CSF and IL-34 show phagocytosis of α-synuclein aggregates and C/EBPβ-dependent proinflammatory activation
(Springer Nature, 2025-02) Llaves López, Andrea; Micoli, Elia; Belmonte Mateos, Carla; Aguilar, Gerard; Alba, Clara; Marsal, Anais; Pulido Salgado, Marta; Rabaneda Lombarte, Neus; Solà i Subirana, Carme; Serratosa i Serdà, Joan; Vidal Taboada, José Manuel; Saura Martí, Josep
Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte–macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein β (C/EBPβ) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPβ plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia–like cells.
Functional remediation improves bipolar disorder functioning with no effects on brain-derived neurotrophic factor levels
(Elsevier B.V., 2019-06) Bonnín Roig, Caterina del Mar; Valls Roig, Èlia; Rosa, Adriane R.; Reinares, María; Jiménez Martínez, Ester; Solé Cabezuelo, Brisa; Montejo Egido, Laura; Meseguer, Ana; Pacchiarotti, Isabella; Colom, Francesc, 1971-; Martínez-Arán, Anabel, 1971-; Tomioka, Yoko; Vieta i Pascual, Eduard, 1963-; Torrent Font, Carla
The main aim of this study is to evaluate the impact of functional remediation (FR) in serum brain derived neurotrophic factor (BDNF) levels in euthymic adult patients with Bipolar Disorder (BD). A total of 128 participants were recruited at the Hospital Clinic of Barcelona. They were assessed at baseline and at the end of follow-up by the means of Hamilton Depression Scale (HAM-D), Young Mania Rating Scale (YMRS) and Functioning Assessment Short Test (FAST), as well as a clinical structured interview to collect clinical and demographic variables of interest. Blood samples were also collected to assess BDNF levels. After baseline assessment, patients received FR, Psychoeducation or treatment as usual (TAU). One hundred and two out of 126 participants finished the study distributed as follows: FR group (n = 39); Psychoeducation group (n = 47) and TAU group (n = 16). Longitudinal repeated-measures analyses addressing the treatment effect on BDNF levels showed non-significant differences between the three groups (Pillai's trace = 0.06; F(2,97)= 0.28; p = 0.75), suggesting no interaction between treatment allocation and time on BDNF levels. The results of this study suggest that FR has no effect on peripheral BDNF levels in euthymic patients with BD, despite the improvement in psychosocial functioning.
Development of Insulin and Leptin Resistance in the Mouse Brainstem with Age
(Humana Press., 2026-01-16) Frutos González, Elvira de; Lauzurica, Nuria; Ochoa Navarro, José Joaquín; García San Frutos, Miriam; Aguado Tomàs, Fernando; Fernández-Agulló, Teresa
Physiological aging involves a progressive deterioration of homeostatic mechanisms that cause obesity and defective glucose homeostasis, which develop age-related diseases increasing mortality risk and reducing lifespan. The brainstem is involved in glucose and metabolic homeostasis by integrating peripheral signals such as insulin and leptin. Here, we evaluated the brainstem response to intracerebroventricular administration of insulin or leptin and the relationship with physiological levels of key molecules implicated in their signal transduction pathway and inflammation in 3-, 6-, and 12-month-old mice which progressively increase adiposity and develop signs of insulin resistance. The initial steps of insulin and leptin signaling pathways decline with age, as well as the protein kinase B (Akt) phosphorylation response. Both hormones decrease the phosphorylation of AMP-activated protein kinase (AMPK) but, while the response to insulin increases with age, the response to leptin decreases in older animals. This insulin and leptin resistance is accompanied by changes in basal protein expression or phosphorylation of insulin and leptin receptors and insulin receptor substrates-1 (IRS-1), as well as the imbalance between basal levels of Akt-phosphorylated and non-phosphorylated protein, without changes in other serine kinases and/or inflammatory pathways such as glycogen-synthase-kinase-3 (GSK3), mammalian targets of rapamycin (mTOR), kinase-p70S6 (p70), protein kinase-C-ε (PKCε), p38 mitogen-activated protein kinase (p38), or c-Janus N-terminal kinase (JNK). High levels of proinflammatory cytokines and glial cell activation suggest the development of neuroinflammation in the brainstem with age, which could mediate the age-associated insulin and leptin resistance and the impairment in glucose and metabolic homeostasis commonly observed in the aging process.
Neuromechanobiology: Bridging Mechanobiology and Neuroscience Through Evidence and Open Questions
(MDPI, 2026-01-19) Zimkowska, Karolina; Riu-Villanueva, Marc; Río Fernández, José Antonio del
Neuromechanobiology has emerged as a multidisciplinary field at the interface of neuroscience and mechanobiology, aiming to elucidate how mechanical forces influence the development, organization, and function of the nervous system. This review offers a comprehensive overview of the historical evolution of the discipline, its molecular and biophysical foundations, and the experimental strategies employed to investigate it. Recent advances have revealed the pivotal roles of substrate stiffness, mechanical signaling, and force transduction in neural stem proliferation, axon guidance, synapse formation, and neural circuit maturation. All these effects originate at the molecular level and extend to the mesoscopic scale. Disrupted mechanotransduction has been increasingly implicated in neurodevelopmental disorders and neurodegenerative diseases, underscoring its clinical relevance. Key unresolved questions and future directions are also highlighted, with emphasis on the need for integrative approaches to decipher the complex interplay between mechanical forces and neural function.
Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer's disease
(BioMed Central, 2021-12-01) Barranco Muñoz, Neus; Plá, Virginia; Alcolea, Daniel; Sánchez Domínguez, Irene; Fischer-Colbrie, Reiner; Ferrer, Isidro (Ferrer Abizanda); Lleó Bisa, Alberto; Aguado Tomàs, Fernando
Background: New fluid biomarkers for Alzheimer's disease (AD) that reveal synaptic and neural network dysfunctions are needed for clinical practice and therapeutic trial design. Dense core vesicle (DCV) cargos are promising cerebrospinal fluid (CSF) indicators of synaptic failure in AD patients. However, their value as biomarkers has not yet been determined. Methods: Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2, carboxypeptidase E (CPE), secretogranins SgIII and SgII, and Cystatin C in the cerebral cortex (n = 45, provided by Bellvitge University Hospital) and CSF samples (n = 66, provided by The Sant Pau Initiative on Neurodegeneration cohort) from AD patients (n = 56) and age-matched controls (n = 55). Results: In AD tissues, most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astrocytes, whereas PC1/3, PC2 and CPE were also specifically accumulated in hippocampal granulovacuolar degeneration bodies. AD individuals displayed an overall decline of secretory proteins in the CSF. Interestingly, in AD patients, the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status. Conclusions: These results demonstrate marked alterations of neuronal-specific prohormone convertases in CSF and cortical tissues of AD patients. The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.
High cognitive reserve in bipolar disorders as a moderator of neurocognitive impairment
(Elsevier B.V., 2017-01-15) Grande i Fullana, Iria; Sánchez-Moreno, José; Solé Cabezuelo, Brisa; Jiménez Martínez, Ester; Torrent Font, Carla; Bonnín Roig, Caterina del Mar; Varo, Cristina; Tabarés-Seisdedos, Rafael; Balanzá-Martínez, Vicent; Valls, Elia; Morilla, Ivette; Carvalho, André F.; Ayuso Mateos, José Luis; Vieta i Pascual, Eduard, 1963-; Martínez-Arán, Anabel, 1971-
Background: Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology, minimize clinical manifestations and successfully complete cognitive tasks. The present study aims to determine whether high CR may constitute a moderator of cognitive functioning in bipolar disorder (BD). Methods: 102 patients with BD and 32 healthy controls were enrolled. All patients met DSM-IV criteria for I or II BD and were euthymic (YMRS≤6 and HDRS≤8) during a 6-month period. All participants were tested with a comprehensive neuropsychological battery, and a Cerebral Reserve Score (CRS) was estimated. Subjects with a CRS below the group median were classified as having low CR, whereas participants with a CRS above the median value were considered to have high CR. Results: Participants with BD with high CR displayed a better performance in measures of attention (digits forward: F=4.554, p=0.039); phonemic and semantic verbal fluency (FAS: F=9.328, p=0.004; and Animal Naming: F=8.532, p=0.006); and verbal memory (short cued recall of California Verbal Learning Test: F=4.236, p=0.046), after multivariable adjustment for potential confounders, including number of admissions and prior psychotic symptoms. Limitations: The cross-sectional design of the study does not allow the establishment of causal inferences. Additionally, the small size of the sample may have limited some results. Conclusions: High cognitive reserve may therefore be a valuable construct to explore for predicting neurocognitive performance in patients with BD regarding premorbid status.
Altered Intra- and Inter-Network Resting-State Functional Connectivity is Associated with Neuropsychological Functioning and Clinical Symptoms in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder
(Wiley, 2025-01-28) Roura, Ignacio; Pardo, Jèssica; Martín Barceló, Cristina; Oltra González, Javier; Campabadal Delgado, Anna; Sala Llonch, Roser; Bargalló Alabart, Núria; Serradell, Mónica; Pont-Sunyer, Claustre; Gaig Ventura, Carles; Mayà, Gerard; Montini, Angelica; Junqué i Plaja, Carme, 1955-; Iranzo, Alex; Segura i Fàbregas, Bàrbara
Background: Isolated rapid-eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha-synucleinopathies. Resting-state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra- and inter-network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear. Objective: To characterize intra- and inter-network rsFC in iRBD patients using a data-driven approach and to assess its associations with clinical features and cognitive functioning. Methods: Forty-two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting-state networks were characterized using independent component analyses. Group differences in intra- and inter-network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses. Results: iRBD patients displayed lower intra-network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non-motor symptoms in iRBD patients. Reduced inter-network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status. Conclusions: iRBD is characterized by both reductions in intra-network rsFC in cortical and subcortical networks and inter-network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra- and inter-network rsFC are associated with cognitive performance and non-motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha-synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Increased translation in adult mouse striatum is sufficient to induce motor dysfunction
(Oxford University Press, 2025-06-19) Castany Pladevall, Carla; Creus Muncunill, Jordi; Bergé-Gardeñes, Maria; Golbano, Arantxa; Brito, Verónica; Pérez Navarro, Ester
Protein synthesis is a process finely regulated in all cell types but specially in neurons as they need rapid changes in protein concentration for synaptic plasticity. Alterations in translation rates have been shown in diseases affecting the brain. In Huntington's disease (HD), an autosomal dominant neurodegenerative disorder characterized by the presence of motor, cognitive and psychiatric symptoms, we have shown that translation is increased in the striatum contributing to motor symptoms. However, very little is known about how translation modulates motor function in physiological conditions. To study this, we overexpressed a constitutively active mutant form of 4E-BP1 (4E-BP1^F113A), a translation repressor, in the striatum of wild-type mice and performed motor tests. One month after striatal injection of adeno-associated viral vectors expressing 4E-BP1^F113A, mice exhibited motor symptoms similar to those observed in the R6/1 HD mouse model. Unexpectedly, de novo protein synthesis and 4E-BP1 phosphorylation were enhanced in the striatum of wild-type mice overexpressing 4E-BP1^F113A. Moreover, the striatum of these animals showed alterations in protein levels of neuronal markers similar to that observed in HD striatum. Altogether, our results indicate that enhanced protein synthesis in the striatum induces neuronal dysfunction and motor symptoms, and reinforce the idea that increased translation is involved in HD pathogenesis.
Sertraline treatment prevents motor dysfunction in a Huntington's disease mouse model and functional decline in patients
(Springer Verlag, 2025-07-25) Garcia-Forn, Marta; Castany-Pladevall, Carla; Creus Muncunill, Jordi; Golbano, Arantxa; Escaramís Babiano, Geòrgia; Pérez Pérez, Jesús; Balantzategi, Uxue; Hernan-Godoy, Marina; Brito, Verónica; Kulisevsky, Jaime; Martí Puig, Eulàlia; Pérez Navarro, Ester
Molecular alterations underlying Huntington's disease (HD) are not fully elucidated and no curative therapies are available. We have described that increased translation efficiency participates in the motor symptoms in the R6/1 HD mouse model. Here, we evaluated whether sertraline, a widely used antidepressant drug, that modulates translation in cancer cells, could ameliorate motor and cognitive symptoms in HD. We also investigated if alterations in translation efficiency occur in fibroblasts from HD patients and serve as a possible biomarker. As an index of translation efficiency levels, we analyzed puromycin incorporation and phosphorylated 4E-BP1 levels in striatal primary cultures and striatum from R6/1 mice, and in HD patients' fibroblasts, with or without sertraline treatment. Motor learning and coordination were analyzed in treated mice by accelerating rotarod, balance beam and vertical pole tests. Clinical data from the Enroll-HD dataset were analyzed to evaluate the potential effects of sertraline treatment in the disease progression. We report that sertraline treatment: 1) modulates translation efficiency in striatal primary neurons expressing mutant huntingtin; 2) prevents motor dysfunction in R6/1 mice and normalizes translation efficiency in the striatum, and 3) delays the decline in functional performance of HD patients. Moreover, puromycin incorporation is increased in fibroblasts from HD patients in a CAG length-dependent manner and is modulated by sertraline treatment. Altogether, our results suggest sertraline as a promising candidate for HD clinical trials to slow down disease progression and that puromycin incorporation in fibroblasts could serve as a pharmacological biomarker for certain treatments
Neurofilament light levels predict clinical progression and death in multiple system atrophy
(Oxford University Press, 2022-07-29) Chelban, Viorica; Nikram, Elham; Pérez-Soriano, Alexandra; Wilke, Carlo; Foubert-Samier, Alexandra; Vijiaratnam, Nirosen; Guo, Tong; Jabbari, Edwin; Olufodun, Simisola; González, Mariel; Senkevich, Konstantin; Laurens, Brice; Péran, Patrice; Rascol, Olivier; Le Traon, Anne Pavy; Todd, Emily G; Costantini, Alyssa A; Alikhwan, Sondos; Tariq, Ambreen; Lin Ng, Bai; Muñoz, Esteban; Painous Martí, Cèlia; Compta, Yaroslau; Junqué i Plaja, Carme, 1955-; Segura i Fàbregas, Bàrbara; Zhelcheska, Kristina; Wellington, Henny; Schöls, Ludge; Jaunmuktane, Zane; Kobylecki, Christopher; Church, Alistair; Hu, Michele T M; Rowe, James B.; Leigh, P Nigel; Massey, Luke; Burn, David J; Pavese, Nicola; Foltynie, Tom; Pchelina, Sofya; Wood, Nicholas; Heslegrave, Amanda J; Zetterberg, Henrik; Bocchetta, Martina; Rohrer, Jonathan D.; Martí Domènech, Ma. Josep; Synofzik, Matthis; Morris, Huw R; Meissner, Wassilios G; Houlden, Henry
Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.
Electrodermal activity in bipolar disorder: Differences between mood episodes and clinical remission using a wearable device in a real-world clinical setting
(Elsevier B.V., 2023-10-21) Anmella, Gerard; Mas, Ariadna; Sanabra González, Miriam; Valenzuela-Pascual, Clàudia; Valentí Ribas, Marc; Pacchiarotti, Isabella; Benabarre, Antonio; Grande i Fullana, Iria; De Prisco, Michele; Oliva, Vincenzo; Fico, Giovanna; Giménez Palomo, Anna; Bastidas, Anna; Agasi, Isabel; Young, Allan H.; Garriga, Marina; Corponi, Filippo; Li, Bryan M.; De Looff, Peter; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego
Background: Bipolar disorder (BD) lacks objective measures for illness activity and treatment response. Electrodermal activity (EDA) is a quantitative measure of autonomic function, which is altered in manic and depressive episodes. We aimed to explore differences in EDA (1) inter-individually: between patients with BD on acute mood episodes, euthymic states and healthy controls (HC), and (2) intra-individually: longitudinally within patients during acute mood episodes of BD and after clinical remission. Methods: A longitudinal observational study. EDA was recorded using a research-grade wearable in patients with BD during acute manic and depressive episodes and at clinical remission. Euthymic BD patients and HC were recorded during a single session. We compared EDA parameters derived from the tonic (mean EDA, mEDA) and phasic components (EDA peaks per minute, pmEDA, and EDA peaks mean amplitude, pmaEDA). Inter- and intra-individual comparisons were computed respectively with ANOVA and paired t-tests. Results: 49 patients with BD (15 manic, 9 depressed, and 25 euthymic), and 19 HC were included. Patients with bipolar depression showed significantly reduced mEDA (p = 0.003) and pmEDA (p = 0.001), which increased to levels similar to euthymia or HC after clinical remission (mEDA, p = 0.011; pmEDA, p < 0.001; pmaEDA, p < 0.001). Manic patients showed no differences compared to euthymic patients and HCs, but a significant reduction of tonic and phasic EDA parameters after clinical remission (mEDA, p = 0.035; pmEDA, p = 0.004). Limitations: Limited sample size, high inter-individual variability of EDA parameters, limited comparability to previous studies and non-adjustment for medication. Conclusion: EDA ecological monitoring might provide several opportunities for early detection of depressive symptoms, and might aid at assessing early response to treatments in mania and bipolar depression.
Level I PD-MCI Using Global Cognitive Tests and the Risk for Parkinson's Disease Dementia
(Wiley, 2022-04-29) Boel, Judith A; MDS Study Group Mild Cognitive Impairment in Parkinson's Disease; de Bie, Rob M A; Schmand, Ben A; Dalrymple-Alford, John C; Marras, Connie; Adler, Charles H; Goldman, Jennifer G; Tröster, Alexander I; Burn, David J; Litvan, Irene; Geurtsen, Gert J
Background: The criteria for PD-MCI allow the use of global cognitive tests. Their predictive value for conversion from PD-MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown. Methods: The MDS PD-MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD-MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD. Results: PD-MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P = <0.001). The C-statistics for MMSE (0.72) and MoCA (0.70) were lower than those based on neuropsychological tests (Level I = 0.82; Level II = 0.81). Sensitivity, specificity and diagnostic accuracy balance was best in Level II. Conclusion: MMSE and MoCA predict conversion to PDD. However, Level II neuropsychological assessment seems the preferred assessment for PD-MCI.

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