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

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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.
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
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.
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, 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.
Mind the gap: The impact of discrepancy between current cognitive function and premorbid intelligence on psychosocial functioning in older age bipolar disorder
(Elsevier B.V., 2025-08-21) Montejo Egido, Laura; Mariegaard Schandorff, Johanna; Zarp, Jeff; Lie Kjærstad, Hanne; Elleby Jespersen, Andreas; Bort, Marta; Ruiz Muñoz, Andrea; Solé Cabezuelo, Brisa; Torrent Font, Carla; Martínez-Arán, Anabel, 1971-; Vieta i Pascual, Eduard, 1963-; Miskowiak, Kamilla W.
Introduction: A discrepancy between current cognitive performance and premorbid IQ may indicate cognitive decline and relate to poorer psychosocial functioning in bipolar disorder, even when cognition appears unimpaired by standard norms. This study examined how objective cognition and IQ-cognition discrepancy relate to psychosocial functioning in older age bipolar disorder (OABD). Methods: OABD underwent neurocognitive assessment, intelligence quotient (IQ) estimation (using vocabulary subtest of WAIS-III), and psychosocial functioning assessment via the Functioning Assessment Short Test (FAST). IQ-cognition discrepancy scores were calculated as the difference between current cognitive performance and estimated premorbid IQ (range: -10 to +10; negative values indicating possible cognitive decline). Linear regressions examined associations between cognition, discrepancy score, and psychosocial functioning. Discriminant analyses evaluated the ability of these scores to predict functional impairment. Results: The sample included 165 participants (116 OABD and 49 healthy controls). Poorer cognitive performance was significantly associated with worse psychosocial functioning (β = -3.38, p = .002). Greater IQ-cognition discrepancy also predicted worse functioning (β = -0.92, p = .04), though cognitive performance showed a stronger association (β = -2.93, p = .017) and better discriminative ability for functional impairment (AUC = 0.75; cut-off = -0.4 SD; sensitivity = 0.69; specificity = 0.72) compared to discrepancy score (AUC = 0.64; sensitivity = 0.39; specificity = 0.87). Conclusions: IQ-cognition discrepancy may serve as a useful idiographic marker of functional impairment in OABD, particularly for individuals with high premorbid IQ. Its use could enhance clinical decision-making and broaden inclusion in pro-cognitive intervention trials.
JNK signaling and its impact on neural cell maturation and differentiation
(Elsevier, 2024-05-25) Castro-Torres, Rubén Darío; Olloquequi, Jordi; Parcerisas, Antoni; Ureña, Jesús; Ettcheto Arriola, Miren; Beas Zárate, Carlos; Camins Espuny, Antoni; Verdaguer, Ester; Auladell i Costa, M. Carme
C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.
The PADRIS-PRESTO Cohort: A Comprehensive Population-Based Study on Mental Health in Catalonia
(Cambridge University Press (CUP), 2025-12-01) De Prisco, Michele; Oliva, Vincenzo; Fico, Giovanna; Mas, Ariadna; Valenzuela-Pascual, Clàudia; Montejo Egido, Laura; Bort, Marta; Sommerhof, Constanza; Bortolozzi, Analia; Miquel Rio, Lluís; Vilella, Elisabet; Forte, Maria Florencia; Fortea, Lydia; Fernández-Plaza, Tábatha; Giménez Palomo, Anna; Sagué-Vilavella, Maria; Madero Gómez, Santiago; Llorca-Bofí, Vicent; Bioque Alcázar, Miquel; Grande i Fullana, Iria; Murru, Andrea; Pacchiarotti, Isabella; Cavero Álvarez, Myriam; Blanch Andreu, Jordi; Viñas-Bardolet, Clara; Aparicio-Nogué, Vicenç; Martínez-Cerdá, Juan Francisco; Parellada Rodón, Eduard; Martínez-Arán, Anabel, 1971-; Radua, Joaquim; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego; Anmella, Gerard
Background: Mental disorders affect nearly 970 million people worldwide, impacting individuals and healthcare systems. Large population databases offer insights often unattainable in smaller studies, but their findings may not always generalize across diverse regions. To address this, we introduce a European cohort from Catalonia, Spain, allowing for comparisons between individuals with mental disorders and the general population. Methods: Data were obtained from the “Programa d’analítica de dades per a la recerca i la innovació en salut” (PADRIS). The cohort included all individuals who accessed public specialized mental health services between 2015 and 2019, with retrospective follow-up extending to 2010. These individuals, referred to as cases, were matched by age, sex, and health region with controls, individuals who had no interactions with mental health services during the same period. Sociodemographic and clinical characteristics, including psychiatric diagnoses, comorbidities, smoking status, healthcare utilization, and prescribed treatments, were analyzed. Results: The study included 1,421,510 individuals (mean age: 41.6±22.1; 53.6% female), with 473,812 cases and 947,698 controls. Cases were more likely to be exempt from income reporting, be ever-smokers, and have musculoskeletal comorbidities. A total of 1,547,374 psychiatric diagnoses were recorded, with anxiety (31.38%) and mood disorders (18.83%) being the most frequent. Over the follow-up, 76.2 million primary care visits and 67.1 million prescriptions were recorded. Conclusions: This cohort enhances our understanding of mental health service use, diagnostic trends, and treatment patterns in Catalonia. The insights derived from this cohort have the potential to inform mental health policies, improving outcomes within and beyond the region.
Eye-tracking metrics during image viewing as possible biomarkers of cognitive alterations: A systematic review and meta-analysis in people with bipolar disorder
(Elsevier B.V., 2025-05-06) De Prisco, Michele ; Oliva, Vincenzo; Fico, Giovanna; Kjærstad, Hanne Lie; Woznica Miskowiak, Kamilla; Anmella, Gerard; Hidalgo Mazzei, Diego; Murru, Andrea; Vieta i Pascual, Eduard, 1963-; Radua, Joaquim
Eye-tracking metrics, such as fixation latency, fixation count, saccade amplitude, and gaze duration, are emerging digital biomarkers that can enhance our understanding of cognitive and emotional alterations in mental disorders. For bipolar disorder (BD), eye-tracking offers a promising approach to investigate the mechanisms underlying the deficits in attention, inhibitory control, and emotion processing. This meta-analysis examined the differences in eye-tracking metrics in individuals with BD compared to healthy controls (HCs) or individuals with other psychiatric conditions, while observing images with emotional or non-emotional content. A comprehensive search of the PubMed/MEDLINE, Scopus, and PsycINFO databases was conducted from inception to August 20, 2024. Studies investigating differences in eye-tracking metrics using an image viewing paradigm were reviewed, and meta-analyses were performed. Ten studies met the inclusion criteria: BD (n = 337) was compared to HCs (n = 352) in all ten studies, to major depressive disorder (n = 60) in two studies, and to schizophrenia (n = 22) in one study. Meta-analyses were only feasible for comparisons between BD and HCs. Individuals with BD exhibited higher latency for the first fixation, a reduced number of fixations, shorter gaze duration, and lower saccadic peak velocity and amplitude. Additionally, they showed shorter fixation durations only when viewing images with negative content. This report provides valuable insights into the cognitive and emotional difficulties faced by individuals with BD, which can guide the development of more targeted and effective assessments and interventions for this population.
Self-utility distance as a computational approach to understanding self-concept clarity
(Springer Science and Business Media LLC, 2025-03-25) García-Arch, Josué; Korn, Christoph W.; Fuentemilla Garriga, Lluís
Self-concept stability and cohesion are crucial for psychological functioning and well-being, yet the mechanisms that underpin this fundamental aspect of human cognition remain underexplored. Integrating insights from cognitive and personality psychology with reinforcement learning, we introduce Self-Utility Distance (SUD)-a metric quantifying the dissimilarities between individuals' self-concept attributes and their expected utility value. In Study 1 (n = 155), participants provided self- and expected utility ratings using a set of predefined adjectives. SUD showed a significant negative relationship with Self-Concept Clarity that persisted after accounting for individuals' Self-Esteem. In Study 2 (n = 323), we found that SUD provides incremental predictive accuracy over Ideal-Self and Ought-Self discrepancies in the prediction of Self-Concept Clarity. In Study 3 (n = 85), we investigated the mechanistic principles underlying Self-Utility Distance. Participants conducted a social learning task where they learned about trait utilities from a reference group. We formalized different computational models to investigate the strategies individuals use to adjust trait utility estimates in response to environmental feedback. Through Hierarchical Bayesian Inference, we found evidence that participants utilized their self-concept to modulate trait utility learning, effectively avoiding the maximization of Self-Utility Distance. Our findings provide insights into self-concept dynamics that might help understand the maintenance of adaptive and maladaptive traits.
Neural correlates of human fear conditioning and sources of variability in 2199 individuals
(Nature Publishing Group, 2025-08-23) Radua, Joaquim; Savage, Hannah S.; Vilajosana, Enric; Jamieson, Alec; Abler, Birgit; Åhs, Fredrik; Beckers, Tom; Cardoner, N. (Narcís); Cisler, Josh M.; Diniz, Juliana B.; Bach, Dominik R.; Elsenbruch, Sigrid; Greening, Steven G.; Holt, Daphne J.; Kaczkurkin, Antonia N.; Keil, Andreas; Kindt, Merel; Koch, Kathrin; LaBar, Kevin S.; Lam, Charlene L.; Larson, Christine L.; Lonsdorf, Tina B.; Merz, Christian J.; McLaughlin, Katie A.; Neria, Yuval; Pine, Daniel S.; Reekum, Carien M. van; Shackman, Alexander J.; Soriano Mas, Carles; Spoormaker, Victor I.; Stout, Daniel M.; Straube, Benjamin; Straube, Thomas; Tuominen, Lauri; Visser, Renée M.; Ahumada, Laura; Arolt, Volker; Batistuzzo, Marcelo C.; Bazán, Paulo R.; Biggs, Emma E.; Cano Català, Marta; Chavarría-Elizondo, Pamela; Cooper, Samuel E.; Dannlowski, Udo; Peña Arteaga, Víctor de la; DeCross, Stephanie N.; Domschke, Katharina; Ehlers, Mana R.; Graner, John L.; Hamm, Alfons O.; Herrmann, Martin J.; Huggins, Ashley A.; Icenhour, Adriane; Juaneda Seguí, Asier; Junghoefer, Markus; Kircher, Tilo; Koelkebeck, Katja; Kuhn, Manuel; Labrenz, Franziska; Lissek, Shmuel M.; Lotze, Martin; Lueken, Ulrike; Margraf, Jürgen; Martínez Zalacaín, Ignacio; Moeck, Robert; Morriss, Jayne; Ortuño, María; Pittig, Andre; Porta Casteràs, Daniel; Richter, Jan; Ridderbusch, Isabelle C.; Rief, Winfried; Roesmann, Kati; Rosén, Jörgen; Rußmann, Alena N.; Sjouwerman, Rachel; Spohrs, Jennifer; Ströhle, Andreas; Suárez Jimenez, Benjamin; Ulrich, Martin; Wittchen, Hans-Ulrich; Zhu, Xi; Waller, Lea; Walter, Henrik; Thompson, Paul M.; Bas Hoogendam, Janna Marie; Groenewold, Nynke A.; Stein, Dan J., 1962-; Van der Wee, N.J.; Dunsmoor, Joseph E.; Marquand, Andre; Harrison, Ben J.; Fullana Rivas, Miguel Àngel
Pavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the “central autonomic–interoceptive” or “salience” network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms
Effectiveness of a Post-discharge Phone-Based Smoking Cessation Intervention for Patients with Severe Mental Health Disorders: The 061 Quitmental Randomized Controlled Clinical Trial
(Springer Verlag, 2024-02-21) Martínez Martínez, Cristina; Feliu, Ariadna; Saura, Judit; Nieva, Gemma; Pinet, Cristina; Raich, Antònia; Mondon, Sílvia; Barrio, Pablo; Andreu, Magalí; Hernández-Ribas, Rosa; Costa, Sílvia; Suelves, Josep Maria; Vilaplana, Jordi; Enríquez, Marta; Alaustre, Laura; Vilalta, Eva; Bonet Alvarez, Judit; Guydish, Joseph; Fernández Muñoz, Esteve; Ballbè i Gibernau, Montse
A pragmatic double-blind randomized controlled trial was conducted in Barcelona to assess a telephone-based smoking cessation intervention's effectiveness for individuals with mental health disorders post-discharge. Participants were divided into an Intervention Group (IG) and Control Group (CG) with a 2:1 allocation ratio. The IG received proactive motivational assistance, while the CG received brief advice. Biochemically validated past 7-day abstinence was the main outcome measure. Of 530 screened individuals, 294 were enrolled (200 IG, 94 CG). During follow-up, participants reported 97 episodes of ≥7-day abstinence (IG: 51, CG: 26). Overall abstinence probability was 30-35%, with no difference between groups at one-year follow-up. However, intervention participants were more likely to report abstinence if they quit during hospitalization or were considering quitting. The intervention effectively supported smoking abstinence in motivated individuals. Combining this with clinical and community-based interventions holds promise for aiding smoking cessation in those with mental disorders
Liver X receptors and inflammatory-induced C/EBPβ selectively cooperate to control CD38 transcription
(Karger, 2024-12-19) Glaría Percaz, Estibaliz; Rodríguez Martínez, Pol; Font Díaz, Joan; Rosa, Juan Vladimir de la; Castrillo, Antonio; Crawshaw, Dylan J.; Vidal Taboada, José Manuel; Saura Martí, Josep; Matalonga, Jonathan; Nunes Chini, Eduardo; Caelles Franch, Carme; Valledor Fernández, Annabel
Introduction: Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages. Methods: Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies. Results: Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ. Conclusion: This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.
Efficacy of pharmacogenetic (PGx)-guided antidepressant treatment on functional outcomes and quality of life in adults with anxiety and affective disorders: A systematic review and meta-analysis
(Elsevier B.V., 2025-08-01) Fares Otero, Natalia Elena; Budde, Monika; Laatsch, Jonathan; Harrer, Mathias; Pelgrim, Teuntje A. D; Philipsen, Alexandra; Heilbronner, Urs; Vieta i Pascual, Eduard, 1963-; Westrhenen, Roos van; PSY-PGx Consortium
We conducted a systematic review and meta-analysis to estimate the efficacy of pharmacogenetic (PGx)-guided antidepressant treatment compared to treatment as usual (TAU) on functional outcomes and quality of life (QoL) in people with anxiety and affective disorders. A PRISMA-compliant systematic search was performed up to 26/06/2025 to identify relevant prospective, randomised controlled trials (RCTs) in seven databases. The revised tool for Risk of Bias (RoB2) was used to assess the methodological qualities of the included studies (PROSPERO CRD42024518683). Of 2774 records, six studies were included comprising 2285 adult patients (PGx group: n = 1395, Mean age = 48.14 years; 55.68 % females; TAU group: n = 890, Mean age = 47.83 years, 58.22 % females). Three studies were included in random-effect meta-analyses. In these, PGx-guided antidepressant treatment significantly decreased functional disability, measured by the Sheehan Disability Scale/Inventory (SDS/I), compared to TAU (k = 3, Mean Difference = -2.85, SE = 1.32 [95 % CI: -5.44, -0.26], p = .031). The Hartung-Knapp adjustment of p-values yielded non-significant effects. Individually, one of these three studies reported a significant effect of PGx-guided treatment on overall SDS score, one on SDI Perceived Social Support partial score, and one no effect. Risk for bias was rated high for one study, with some concerns for the other five. Due to the small number of included trials, our ability to conduct analyses of heterogeneity, moderators and publication bias was limited. Nonetheless, our results suggest that PGx-guided antidepressant treatment may improve functioning in people with anxiety and affective disorders.
Diffusivity alterations related to cognitive performance and phenylalanine levels in early-treated adults with phenylketonuria
(Springer, 2025-07-02) Pardo, Jèssica; Capdevila Lacasa, Clara; Segura i Fàbregas, Bàrbara; Pané, Adriana; Moreno Lozano, Pedro; Garrabou Tornos, Glòria; Grau Junyent, Josep M. (Josep Maria); Junqué i Plaja, Carme, 1955-; Consortium PKU.cat
Background Altered white matter (WM) is consistently reported in patients with phenylketonuria (PKU). However, the knowledge about WM microstructural integrity in early-treated adults with classical PKU and its relationship with cognition and metabolic parameters is inconclusive. This study aims to explore the cerebral WM microstructural alterations in adult patients with early-treated classical PKU and their association with blood phenylalanine (Phe) levels and neuropsychological performance using whole-brain diffusion tensor imaging (DTI). Methods Twenty-nine patients with early-treated classical PKU (mean age = 30.86, SD = 7.74) and 31 healthy controls (mean age = 32.45, SD = 9.40) underwent neuropsychological assessment and MRI. Phe dry blood spot (DBS-Phe) samples, along with venous Phe levels, were collected from the PKU sample to calculate the index of dietary control (IDC). Tract-based spatial statistics (TBSS) of the mean diffusivity (MD), and fractional anisotropy (FA), were carried out with FSL v6.0.4 to assess between-group differences and to explore associations with both cognitive and clinical data. Results Patients exhibited a widespread white matter tract involvement, with lower MD and higher FA values compared to controls. The most affected tracts were the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus for MD, and the anterior corona radiata, uncinate fasciculus and forceps minor for FA. MD negatively correlated with IDC and venous Phe levels, whereas FA negatively correlated with full-scale intelligence quotient (FSIQ) (p-value ≤0.05 FWE-corrected). Conclusions Microstructural WM alterations were present in adults with early-treated classical PKU, and these abnormalities were related to global intelligence and metabolic control markers. Although our results suggest the importance of proper disease management, further studies are needed to determine its long-term relevance.
Educational attainment does not influence brain aging
(National Academy of Sciences, 2021-05-21) Nyberg, Lars; Magnussen, Fredrik; Lundquist, Anders; Baare, William; Bartrés Faz, David; Bertram, Lars; Boraxbekk, Carl Johan; Brandmaier, Andreas M.; Drevon, Christian A; Ebmeier, Klaus P.; Ghisletta, Paolo; Henson, Richard N.; Junqué i Plaja, Carme, 1955-; Kievit, Rogier; Kleemeyer, Maike; Knights, Ethan; Kühn, Simone; Lindenberger, Ulman; Penninx, Brenda W. J. H.; Pudas, Sara; Sørensen, Øystein; Vaqué Alcázar, Lídia; Walhovd, Kristine B.; Fjell, Anders Martin
Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain agin
Triangulating the associations of different types of childhood adversity and first-episode psychosis with cortical thickness across brain regions
(Cambridge University Press (CUP), 2024-12-16) Fares Otero, Natalia Elena; Verdolini, Norma; Melero, Helena; Andrés Camazón, Pablo; Vilajosana, Enric; Cavone, Vito; García Bueno, Borja; Rapado Castro, Marta; Izquierdo, Ana; Martín Hernández, David; Mola Cárdenes, Pablo; Leal Leturia, Itziar; Dompablo Tobar, Mónica; Ortiz Tallo, Ana; Martínez Gras, Isabel; Muñoz Sanjose, Ainoa; Loeck de Lapuerta, Carmen; Rodriguez Jimenez, Roberto; Díaz-Marsá, Marina; Bravo Ortiz, María Fe; Ibañez, Angela; Baca García, Enrique; Vieta i Pascual, Eduard, 1963-; Ayuso Mateos, José Luis; Malpica, Norberto; Arango López, Celso; Díaz Caneja, Covadonga M.; Radua, Joaquim
Background Both childhood adversity (CA) and first-episode psychosis (FEP) have been linked to alterations in cortical thickness (CT). The interactive effects between different types of CAs and FEP on CT remain understudied. Methods One-hundred sixteen individuals with FEP (mean age = 23.8 ± 6.9 years, 34% females, 80.2% non-affective FEP) and 98 healthy controls (HCs) (mean age = 24.4 ± 6.2 years, 43% females) reported the presence/absence of CA <17 years using an adapted version of the Childhood Experience of Care and Abuse (CECA.Q) and the Retrospective Bullying Questionnaire (RBQ) and underwent magnetic resonance imaging (MRI) scans. Correlation analyses were used to assess associations between brain maps of CA and FEP effects. General linear models (GLMs) were performed to assess the interaction effects of CA and FEP on CT. Results Eighty-three individuals with FEP and 83 HCs reported exposure to at least one CA. CT alterations in FEP were similar to those found in participants exposed to separation from parents, bullying, parental discord, household poverty, and sexual abuse (r = 0.50 to 0.25). Exposure to neglect (β = −0.24, 95% CI [−0.37 to −0.12], p = 0.016) and overall maltreatment (β = −0.13, 95% CI [−0.20 to −0.06], p = 0.043) were associated with cortical thinning in the right medial orbitofrontal region. Conclusions Cortical alterations in individuals with FEP are similar to those observed in the context of socio-environmental adversity. Neglect and maltreatment may contribute to CT reductions in FEP. Our findings provide new insights into the specific neurobiological effects of CA in early psychosis.
Identifying digital biomarkers of illness activity and treatment response in bipolar disorder with a novel wearable device (TIMEBASE): protocol for a pragmatic observational clinical study
(Cambridge University Press (CUP), 2024-08-01) Anmella, Gerard; Corponi, Filippo; Li, Bryan M.; Mas, Ariadna; Garriga, Marina; Sanabra González, Miriam; Pacchiarotti, Isabella; Valentí Ribas, Marc; Grande i Fullana, Iria; Benabarre, Antonio; Giménez Palomo, Anna; Agasi, Isabel; Bastidas Salvadó, Anna; Cavero Álvarez, Myriam; Bioque Alcázar, Miquel; García Rizo, Clemente; Madero Gómez, Santiago; Arbelo, Néstor; Murru, Andrea; Amoretti Guadall, Silvia; Martínez-Arán, Anabel, 1971-; Ruiz, Victoria; Rivas, Yudith; Fico, Giovanna; De Prisco, Michele; Oliva, Vincenzo; Solanes, Aleix; Radua, Joaquim; Samalin, Ludovic; Young, Allan H.; Vergari, Antonio; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego
Background Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions. Aims The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder. Method We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania (n = 12), depression (n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features (n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients. Results Recruitment is ongoing. Conclusions This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.
Efficacy of psychosocial interventions on social functioning in individuals with childhood maltreatment experiences: a protocol for a systematic review and network meta-analysis
(Taylor & Francis, 2025-06-06) Fares Otero, Natalia Elena; Amoretti Guadall, Silvia; Solé Cabezuelo, Brisa; Halligan, Sarah L.; Vieta i Pascual, Eduard, 1963-; Leucht, Stefan; Seedat, Soraya; Harrer, Mathias
[eng] Background: Several psychosocial interventions have shown promising effects in treating people affected by childhood maltreatment (CM); however, their comparative efficacy on social functioning remains largely unknown. To address this issue, a systematic review and network meta-analysis (NMA) will be conducted to investigate the comparative efficacy of different psychosocial interventions on global social functioning and specific domains of social functioning, including behavioural, emotional, cognitive and physiological processes. We aim to develop a hierarchical ranking of existing psychosocial interventions concerning their efficacy and acceptability which could inform treatment guidelines. Methods: Randomised controlled trials (RCTs) investigating psychosocial interventions for individuals with exposure to CM when they were younger than age 18 will be included. Primary outcomes will be global and domains of social functioning (measured up to 3, 6, 12 months and at the longest follow-up). Study drop-out will be a secondary outcome that will serve as a measure of acceptability. Study selection and data extraction will be performed by at least two independent reviewers. We will assess the risk of bias for each study using the Cochrane Risk of Bias tool 2 (RoB2) and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). The effects of potential moderators, such as age (children/adolescents vs. adults), population type (clinical vs. non-clinical samples), or sex (% males), socioeconomic status (low-income vs. middle-high-income countries), and intervention characteristics (individual vs. group training, number of sessions) will be analysed using subgroup-analyses or meta-regressions. Other candidate moderators/mediators (personality, post-traumatic symptoms, brain structure/function, cognitive reserve) will also be explored and narratively summarised. Sensitivity analyses will be conducted to explore further heterogeneity and assess the robustness of our findings. Discussion: This systematic review and NMA aims to compare multiple existing psychosocial interventions in individuals affected by CM and establish the relative rankings of these interventions for social functioning. Our results may provide practical guidance concerning the most effective psychosocial interventions to reduce the societal burden associated with CM.

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