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- ItemInter-brain synchrony in social interactions: Underlying mechanism or epiphenomenon?(2025) Leiva Cisterna, Ivo Pablo Andrés; Rodríguez B., Eugenio; Pontificia Universidad Católica de Chile. Facultad de Medicina; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas; Pontificia Universidad Católica de Chile. Facultad de Ciencias Sociales; Pontificia Universidad Católica de Chile. Facultad de Química y FarmaciaEl estudio de la dinámica cerebral durante las interacciones sociales ha aumentado considerablemente en las últimas décadas. Con el surgimiento del hyperscanning – una técnica para el registro simultáneo de múltiples individuos, los estudios en neurociencia social han encontrado consistentemente acoplamiento neural entre individuos que interactúan. Este creciente cuerpo de evidencia sugiere que la sincronía inter-cerebral podría tener un rol facilitador de las interacciones sociales, aunque la mayoría de la evidencia disponible es correlacional. La falta de evidencia causal ha levantado dudas acerca de si la sincronía inter-cerebral podría ser un epifenómeno producto del procesamiento neuronal concurrente de estímulos similares más que un mecanismo neuronal relevante para las interacciones sociales.En consecuencia, actualmente existe una brecha en nuestra comprensión de la dinámica neural de la conducta social, específicamente de tipo cooperativo, relacionada a la relevancia funcional de la sincronía inter-neuronal. Aunque algunos estudios han intentado inducir estados prosociales o aumentar la coordinación conductual de forma experimental, actualmente no existe evidencia causal vinculando directamente la sincronía neural con la conducta cooperativa.La presente tesis doctoral aborda la pregunta por el rol funcional de la sincronía inter-cerebral estableciendo un marco causal para medir cambios conductuales provocados por manipulaciones experimentales de la sincronía. Aquí utilizamos una tarea cooperativa clásica e implementamos por primera vez un paradigma de encarrilamiento sensorial dual (dual sensory entrainment), siguiendo la propuesta de estimulación multi-cerebro (multi-brain stimulation) para manipular la sincronía inter-cerebral de díadas que cooperan y evaluar si esto lleva a cambios en su rendimiento.Basándonos en investigaciones previas, se aplicó encarrilamiento sensorial dual a díadas en dos frecuencias diferentes (16 y 40 Hz) bajo distintos protocolos de estimulación. Nuestra hipótesis fue que, si la sincronía inter-cerebral sirve como mecanismo funcional para la cooperación, entonces un encarrilamiento visual dual que conduce a una mayor sincronía inter-cerebral debería resultar en tasas de cooperación más altas en comparación con una condición control en la que el encarrilamiento no aumenta la sincronía intercerebral. Además, las tasas de cooperación también deberían ser más altas en comparación con un grupo control que realiza la misma tarea sin el encarrilamiento. Por el contrario, si la sincronía inter-cerebral es simplemente un epifenómeno, no deberían surgir diferencias significativas en cooperación entre las condiciones y los grupos, a pesar de las diferencias en la sincronía inter-cerebral.Nuestros resultados muestran que la inducción de sincronía inter-cerebral aumenta la tasa de cooperación de las díadas en comparación al grupo control, siendo la estimulación en frecuencias beta (16 Hz) la que produce el efecto más prominente. Este aumento no puede atribuirse a diferencias en los tiempos de reacción, sino a una mejor coordinación entre los participantes. Además, en lugar de aumentar aleatoriamente la probabilidad de cooperar, el encarrilamiento en la banda beta indujo estados estables de acoplamiento conductual que permitieron a los participantes mantener la coordinación por periodos prolongados. Estos hallazgos pueden explicarse por la hipótesis de que las oscilaciones beta mantienen el statu quo sensoriomotor y la teoría de la predicción mutua de la conducta social, conectando teorías clásicas de la neurociencia cognitiva con modelos recientes de la neurociencia social. Por otro lado, la estimulación en frecuencias gamma (40 Hz) no produjo diferencias conductuales con respecto al grupo control. Esto puede atribuirse a inconsistencias en los efectos neuronales inducidos por la estimulación, dando lugar a una discusión sobre los parámetros óptimos para estimular las oscilaciones en la banda gamma y su posible efecto en el comportamiento.Inesperadamente, nuestras principales condiciones de encarrilamiento no se diferenciaron significativamente de las condiciones control, en las que la estimulación se presentó asincrónicamente a los participantes. Si bien esto podría discutirse en términos metodológicos, sugiriendo limitaciones para lograr una asincronía real, nuestra explicación alternativa cuestiona el papel de la fase oscilatoria en las interacciones sociales. Por lo tanto, sugerimos roles diferenciales para la sincronía de fase fija (phase-locked, con diferencias de fase constante) como una forma general de sincronía y para la sincronía en fase (in-phase, con diferencias de fase cero) como un caso especial de sincronía de fase fija.En conjunto, estos resultados apoyan la definición mecanicista de la sincronía inter-cerebral. Proporcionamos evidencia causal robusta de la especificidad funcional de este mecanismo para facilitar la conducta cooperativa.
- ItemClinical epidemiology: Optimization of eradication treatment for Helicobacter Pylori in Latin America and Chile(2025) Medel-Jara, Patricio Andrés; Riquelme Pérez, Arnoldo; Pontificia Universidad Católica de Chile. Escuela de Salud PúblicaEsta tesis doctoral en Epidemiología aborda la optimización del tratamiento de H. pylori en Chile y Latinoamérica para prevenir el cáncer gástrico. A través del estudio multicéntrico LEGACY y un ensayo clínico aleatorizado, se demostró que la terapia cuádruple optimizada con bismuto supera significativamente a la triple estándar (erradicación >90% vs. <82%). Se concluye que la terapia cuádruple debe ser el tratamiento empírico de primera línea en la región por su alta efectividad clínica.
- ItemDirect manipulation of conscious visual perception by real-time fMRI multivoxel pattern decoded neurofeedback of frontoparietal brain activity(2025) Amaro Fuenzalida, Juan Ignacio; Ossandón, Tomás; Sitaram, Ranganatha; Pontificia Universidad Católica de Chile. Facultad de Medicina; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas; Pontificia Universidad Católica de Chile. Facultad de Ciencias Sociales; Pontificia Universidad Católica de Chile. Facultad de Química y FarmaciaThe present study addresses the problem of consciousness from the perspective of its phenomenological content (awareness). It examines the main contemporary theories concerning the neural correlates of consciousness, focusing on the Global Neuronal Workspace Model (GNWM) and the Higher-Order Theory (HOT). While the GNWM proposes that conscious access arises from the propagation of sensory information toward frontoparietal networks—particularly the dorsolateral prefrontal cortex—HOT suggests that consciousness emerges when a sensory representation is meta-represented by a higher-order representation localized in frontal regions. The former explains conscious access as a process of amplification and global broadcasting of information, whereas the latter attributes to the frontal cortex a constitutively representational role, capable of generating a conscious version of sensory inputs.Building on these perspectives, the present work aims to examine whether frontoparietal neural representations maintain an identity relationship with the subjective experience of visual stimuli, following the Neural Identity Theory (NIT), which posits that mental states and neural patterns are coextensive—two descriptions of the same phenomenon. This hypothesis was evaluated experimentally through functional magnetic resonance imaging (fMRI) and multivoxel pattern analysis (MVPA) during a Directional Motion Detection Task (DMDT).The study tested two main hypotheses: (1) frontoparietal activity varies as a function of stimulus ambiguity, being modulated by signal strength (coherence); and (2) the decodability of frontoparietal patterns provides evidence of an identity relationship between subjective experience and neural representation.The results showed that frontal activity increased under ambiguous conditions, indicating that when the stimulus was difficult to discriminate, frontal regions actively contributed to the construction of conscious experience through attentional and metarepresentational mechanisms. This involvement included the dorsolateral prefrontal, orbitofrontal, anterior cingulate, and opercular cortices.Notably, MVPA results revealed that even during trials without conscious report, information about motion direction could be decoded from patterns in the orbitofrontal and temporal cortices. This suggests that the brain maintains representations of stimuli even in the absence of conscious access. When sensory information was insufficient, participants appeared to rely on reconstructive or inferential processes dependent on memory, integrating perceptual fragments with stored knowledge. This pattern suggests that conscious experience depends not only on stimulus features but also on previous experience and the history of interactions with the environment.Taken together, these findings support a representational and integrative view of consciousness, in which the frontal cortex not only facilitates access to information but also contributes to its construction.
- ItemNon-invasive diagnostic for steatotic liver disease: a proposal for primary health care(2025) Spencer Sandino, María de los Ángeles; Ferreccio Readi, Catterina; Barrera Martínez, Francisco; Pontificia Universidad Católica de Chile. Escuela de MedicinaSteatotic Liver Disease (SLD), formerly known as “fatty liver,” is the most common chronic liver condition worldwide, capable of progressing silently from simple steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma. In June 2023, an international consensus led by Rinella et al. redefined this spectrum under the umbrella term SLD, with subcategories including MASLD (Metabolic Dysfunction Associated Steatotic Liver Disease), MetALD (Metabolic Dysfunction Associated Alcohol Related Liver Disease), ALD (Alcohol Related Liver Disease), Specific aetiologies, and cryptogenic. MASLD, driven by obesity, type 2 diabetes, and hypertension, now affects roughly one quarter of adults globally, and in Chile, its prevalence more than doubled from about 23 % in 2000 to nearly 48 % in 2019, mirroring national increases in metabolic risk factors. Because MASLD and related phenotypes are often clinically silent until advanced stages, late diagnosis incurs higher healthcare costs, delays treatment, and worsens outcomes. Lifestyle modification, diet, exercise, and weight loss remain the cornerstone of early management but are increasingly ineffective as fibrosis advances. In the absence of systematic screening programs in Chile’s primary healthcare system, many at-risk individuals go unidentified until complications arise. To address this, the thesis developed and validated non-invasive diagnostic strategies tailored for resource-limited primary care settings, decentralizing detection and enabling timely intervention. Using two large cohorts—the rural Maule Cohort (MAUCO) of 9,013 adults aged 40–74 and the Chile Biliary Longitudinal Study (Chile BiLS) of over 4,338 women with gallstone disease—the work first showed that applying the new SLD classification identifies additional high risk individuals missed by NAFLD and MAFLD criteria, uncovering metabolic profiles linked to elevated fibrosis and cardiovascular risk. Standardized ultrasound readings in Chile BiLS, supported by rigorous training protocols, achieved substantial intra-observer consistency and acceptable inter-observer agreement, demonstrating that point of care ultrasound can reliably serve as a first-line screening tool. Finally, in a nested MAUCO+ trial of 456 high-risk participants, two logistic regression models were developed—one based solely on anthropometry and routine laboratory tests (age, sex, BMI, waist circumference, lipids, insulin, CRP, and ALT) and another incorporating ultrasound. Both models outperformed the Fatty Liver Index: the non-imaging model achieved 81 % sensitivity and 71 % specificity (AUC = 0.79), while the imaging-enhanced model reached 92 % sensitivity and 71 % specificity (AUC = 0.88). By demonstrating that the SLD framework more inclusively identifies those at risk, that ultrasound can be reliably deployed in primary care, and that simple predictive algorithms yield high diagnostic accuracy, this thesis offers a practical roadmap for integrating SLD screening into Chile’s health system. Decentralized, algorithm-driven detection can facilitate early lifestyle interventions, slow disease progression, optimize resource allocation, and ultimately reduce liver-related morbidity and mortality, supporting policy shifts toward nationwide screening initiatives and serving as a model for other Latin American countries facing rising metabolic and hepatic disease.
- ItemEarly inhibition of the ATX-LPA axis modulates YAP/TAZ signaling and mitigates dystrophic progression in δ-SACOGLYCANOPATHY mice(2025) Gutierrez Rojas, Cristian Armando; Carvajal Cabrera, Jorge; Brandan, Enrique; Pontificia Universidad Católica de Chile. Escuela de MedicinaSarcoglycanopathies, a type of limb girdle muscle dystrophy, are caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma. This leaves muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses, resulting in muscle weakness and atrophy. In different tissues, two signaling pathways have been implicated in inflammation and fibrosis: autotaxin-lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. The two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes and pathways in the development of sarcoglycanopathy or the effect of early inhibition of this axis has been evaluated in skeletal muscle.Using the δ-sarcoglycan knockout mouse model (Sgcd-/-), the study investigated components of these pathways, muscle regeneration, inflammatory and fibrotic responses, and muscle function of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) during the development of δ sarcoglycanopathy in the first two months of life. In addition, the effect of early ATX-LPA axis inhibition on inflammatory profile, ECM component deposition, muscle function and regenerative capacity was evaluated using PF8380 (ATX inhibitor) and Ki16425 (LPA1 antagonist). Sgcd-/- mice showed early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Early impairments in force generation in the TA and EDL, resistance to mechanical damage in the EDL, and running ability were also observed in these mice. Furthermore, these animals showed early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the muscles. Interestingly, inhibition of the ATX-LPA axis with either inhibitor modulated YAP/TAZ signaling, ameliorated the inflammatory and fibrotic response in the muscle studied, and improved muscle performance and running ability in Sgcd-/- mice.This study provides compelling evidence that the ATX-LPA axis and YAP/TAZ signaling pathway are dysregulated in skeletal muscle of Sgcd-/- mice from an early age. These molecular alterations coincide with the development of fibrotic and inflammatory responses in this disease model. Importantly, our findings demonstrate that targeted inhibition of either ATX or LPA1 results in significant amelioration of these pathological processes. These results not only advance our understanding of the molecular mechanisms underlying muscular dystrophy but also identify the ATX-LPA axis as a promising therapeutic target for intervention.