3,259 research outputs found

    The representation of priors and decisions in the human parietal cortex

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    Animals actively sample their environment through orienting actions such as saccadic eye movements. Saccadic targets are selected based both on sensory evidence immediately preceding the saccade, and a “salience map” or prior built-up over multiple saccades. In the primate cortex, the selection of each individual saccade depends on competition between target-selective cells that ramp up their firing rate to saccade release. However, it is less clear how a cross-saccade prior might be implemented, either in neural firing or through an activity-silent mechanism such as modification of synaptic weights on sensory inputs. Here, we present evidence from magnetoencephalography for 2 distinct processes underlying the selection of the current saccade, and the representation of the prior, in human parietal cortex. While the classic ramping decision process for each saccade was reflected in neural firing rates (measured in the event-related field), a prior built-up over multiple saccades was implemented via modulation of the gain on sensory inputs from the preferred target, as evidenced by rapid frequency tagging. A cascade of computations over time (initial representation of the prior, followed by evidence accumulation and then an integration of prior and evidence) provides a mechanism by which a salience map may be built up across saccades in parietal cortex. It also provides insight into the apparent contradiction that inactivation of parietal cortex has been shown not to affect performance on single-trials, despite the presence of clear evidence accumulation signals in this region

    Characterising feedback to mid-level visual cortex during perceptual decision-making

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    A long-standing question in neuroscience is how the activity of visual neurons supports perception. Historically examined from a purely feedforward perspective, this approach documented neuronal selectivity for specific perceptual features, sensitivity akin to an animal’s perceptual sensitivity and demonstrated causal effects of sensory neurons on an animal’s decision. Indeed, even the variable activity of single sensory neurons was found to be correlated with the decision an animal would make, often referred to as ‘choice probability’. This decision-related activity was long interpreted as reflecting the causal effect of feedforward noise on the decision process, but increasing evidence has pointed to a feedback origin of these correlations with behaviour. However the role of that such feedback remains unclear. The work in this thesis sought to investigate the nature of this feedback in order to help explain what it’s potential role in perceptual-decision making may be, as well as to further clarify long-held beliefs on the origin of decision-related activity. To do so, we focussed on the mechanisms underlying disparity perception in disparity-selective mid-level visual areas. First, we tested whether neurons in area V2 were causally involved in a disparity discrimination task. By electrically stimulating disparity-selective V2 neurons, we demonstrated a bias in the animals’ decisions in line with the preference of the stimulated neurons, suggesting a causal role for these neurons in disparity perception. We then proceeded to better characterise the feedback that gives rise to decision-related activity in these neurons, as well as another group of disparity-selective neurons in V3/V3a. Since feedback has often been assumed to selectively target visual neurons based on their relevance for the task or stimulus demands, we aimed to test the extent of this selectivity. To do so, we employed a novel task combining disparity discrimination with a spatial attention component, wherein animals had to ignore one stimulus whilst discriminating the other. Critically, this led to distinct predictions for decision-related activity depending on how selective the feedback would be. We found that decision-related activity could be observed for neurons representing an ignored task-irrelevant stimulus, incompatible with accounts of feedback which exclusively target task-relevant neurons. Our findings suggest that decision-related activity arises predominantly as a result of feedback targeting neurons selective for disparity, regardless of whether they contribute to the task. Importantly they imply a biological constraint to the selectivity of feedback, and demand a revision of current theoretical accounts of feedback in perceptual decision-making. The work presented here thus not only contributes to our understanding of disparity perception, but has critical implications for how feedback modulates the responses of visual neurons and ultimately shapes perception

    Electrophysiological hallmarks for event relations and event roles in working memory

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    The ability to maintain events (i.e., interactions between/among objects) in working memory is crucial for our everyday cognition, yet the format of this representation is poorly understood. The current ERP study was designed to answer two questions: How is maintaining events (e.g., the tiger hit the lion) neurally different from maintaining item coordinations (e.g., the tiger and the lion)? That is, how is the event relation (present in events but not coordinations) represented? And how is the agent, or initiator of the event encoded differently from the patient, or receiver of the event during maintenance? We used a novel picture-sentence match-across-delay approach in which the working memory representation was “pinged” during the delay, replicated across two ERP experiments with Chinese and English materials. We found that maintenance of events elicited a long-lasting late sustained difference in posterior-occipital electrodes relative to non-events. This effect resembled the negative slow wave reported in previous studies of working memory, suggesting that the maintenance of events in working memory may impose a higher cost compared to coordinations. Although we did not observe significant ERP differences associated with pinging the agent vs. the patient during the delay, we did find that the ping appeared to dampen the ongoing sustained difference, suggesting a shift from sustained activity to activity silent mechanisms. These results suggest a new method by which ERPs can be used to elucidate the format of neural representation for events in working memory

    Signatures of hierarchical temporal processing in the mouse visual system

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    A core challenge for information processing in the brain is to integrate information across various timescales. This could be achieved by a hierarchical organization of temporal processing, as reported for primates; however, it is open whether this hierarchical organization generalizes to sensory processing across species. Here, we studied signatures of temporal processing along the anatomical hierarchy in the mouse visual system. We found that the intrinsic and information timescales of spiking activity, which serve as proxies for how long information is stored in neural activity, increased along the anatomical hierarchy. Using information theory, we also quantified the predictability of neural spiking. The predictability is expected to be higher for longer integration of past information, but low for redundancy reduction in an efficient code. We found that predictability decreases along the anatomical cortical hierarchy, which is in line with efficient coding, but in contrast to the expectation of higher predictability for areas with higher timescales. Mechanistically, we could explain these results in a basic network model, where the increase in timescales arises from increasing network recurrence, while recurrence also reduces predictability if the model's input is correlated. The model thus suggests that timescales are mainly a network-intrinsic effect, whereas information-theoretic predictability depends on other sources such as (correlated) sensory stimuli. This is supported by a comparison of experimental data from different stimulus conditions. Our results show a clear hierarchy across mouse visual cortex, and thus suggest that hierarchical temporal processing presents a general organization principle across mammals.Comment: 20 pages, 4 figure

    Analysis of the impact of synaptic plasticity genes and Human Accelerated Regions on brain function and structure: from the healthy brain to schizophrenia

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    [eng] Schizophrenia is a severe psychiatric disorder affecting around 24 million people worldwide. While we begin to disentangle the biological actors implicated in the origin of the disorder, the precise aetiological mechanisms remain largely unknown. Therefore, psychiatry research efforts still need to focus on a better understanding of the complex biological foundations of the disorder to achieve more precise diagnoses and the development of novel therapeutic strategies improving the patients’ quality of life. The prevailing etiopathological hypothesis considers that schizophrenia originates from the interplay between subtle genetic and environmental insults that disrupt the perfectly orchestrated mechanisms guiding neurodevelopment. Additionally, from an evolutionary perspective, it is suggested that schizophrenia represents a costly trade-off in the evolution of human-specific ontogenic neurodevelopmental processes sustaining the inherent complexity and variability of brain functioning, cognition, and behaviour. Along the neurodevelopmental process, the synapse formation and the organisation and maturation of neural circuits anchor the emergence of distinctive human cortical brain functions. In turn, multidisciplinary evidence indicates that synaptic alterations participate in brain dysfunctions, eventually leading to the emergence of the symptoms and cognitive deficits of schizophrenia. Accordingly, it is suggested that synaptic plasticity impairments play a critical role in the pathophysiology of the disorder. Among genes converging in neurodevelopmental and synaptic plasticity pathways, there are genes mediating signalling pathways involved in neural homeostasis, dendritic spine development and neural excitability, such as KCNH2, DISC1, CACNA1C and ZNF804A, all of them previously associated with the risk for schizophrenia. Moreover, evolutionary approaches have identified regions that accumulated human-specific changes since the divergence from chimpanzees, like Human Accelerated Regions (HARs). These regions act as transcriptional regulatory elements that endow human neurodevelopment with unique characteristics and harbour schizophrenia genetic susceptibility variants. To facilitate the identification of the genetic and biological mechanisms involved in schizophrenia aetiology, the use of brain-based intermediate phenotypes is a valuable strategy. Following two approaches centred on the genetic-phenotypic correlates of synaptic plasticity candidate genes and HARs sequences in the brain-based alterations in schizophrenia, this thesis includes four original articles and one systematic review. In these articles, we report the effect of common polymorphisms in KCNH2, DISC1, CACNA1C and ZNF804A genes and the polygenic load of HARs-informative sets on the differences observed between healthy brains and brains with schizophrenia. Overall, the results validate the efficacy of neuroimaging phenotypes to identify the genetic determinants of schizophrenia and point out the complementarity of candidate genes and genome-wide approaches in the study of the genetic architecture of the disorder. First, we describe the role of KCNH2 and DISC1 genetic variability in modulating the attentional and working memory-related functional responses in a diagnosis- dependent manner. Furthermore, we identify that the epistasis between two schizophrenia GWAS-associated genes, CACNAC1C and ZNF804A, influence the functional ability to adapt to increased working memory difficulty euqally in healthy controls and patients with schizophrenia. Second, we present a review of how HARs underlie human neurodevelopmental signatures, brain configuration, functioning and susceptibility behind psychiatric disorders. Likewise, we report the modulatory effect of HARs polygenicity on brain cortical architectural differences in schizophrenia and provide evidence on the importance of foetal-active regulatory HARs in patients' cortical surface area variability. Globally, the findings exposed in this thesis point towards the fact that the aetiological foundations of schizophrenia are related to the individual genetic differences altering neurodevelopment and synaptic plasticity trajectories but also to the genomic make-up that defines us as a species. This thesis provides a drop in the ocean of knowledge on disorders inherently linked to the human condition and has sought to comprehend the unique characteristics of our brain to help unravel what it means to be human.[cat] L’esquizofrènia és un trastorn neuropsiquiàtric greu que afecta a 24 milions de persones a tot el món. Tot i que comencem a conèixer els mecanismes biològics implicats en l’origen del trastorn, els processos etiològics precisos continuen essent en gran part desconeguts. Per tant, els esforços en la recerca encara necessiten dirigir-se en millorar el coneixement dels fonaments biològics del trastorn, per tal d’aconseguir un diagnòstic més precís i el desenvolupament de noves estratègies terapèutiques que millorin la qualitat de vida dels pacients. La hipòtesi etiopatogènica predominant considera que el trastorn s’origina a partir de la interacció entre factors genètics i ambientals que pertorben els mecanismes perfectament orquestrats que guien el neurodesenvolupament. A més, des d’una perspectiva evolutiva, s’ha suggerit que l’esquizofrènia representaria el “preu a pagar” per evolució dels processos ontogènics específicament humans que sustenten la complexitat i la variabilitat inherent al funcionament del cervell, la cognició i el comportament de la nostra espècie. Al llarg del neurodevenvolupament, la formació de sinapsis i l’organització i maduració dels circuits neurals ancoren l’aparició de funcions cerebrals corticals distintivament humanes. Al seu torn, evidències multidisciplinàries indiquen que les alteracions sinàptiques participen en disfuncions cerebrals que tenen com a resultat l’aparició dels símptomes cognitius i clínics de l’esquizofrènia. En conseqüència, s’ha proposat que les alteracions de la plasticitat sinàptica tenen un paper crític en la fisiopatologia del trastorn. Entre els gens que conflueixen en vies del neurodesenvolupament i de plasticitat sinàptica, hi ha gens que participen en vies de senyalització implicades en l’homeòstasi neuronal, el desenvolupament de les espines dendrítiques i l’excitabilitat neuronal, com els gens KCNH2, el DISC1, el CACNA1C i el ZNF804A, tots prèviament associats amb el risc per a l’esquizofrènia. A més, aproximacions evolutives han identificat regions que han acumulat canvis específicament en humans des de la divergència amb els ximpanzés, com les Regions Humanes Accelerades (o Human Accelerated Regions, HARs en anglès). Aquestes regions actuen com a elements reguladors de la transcripció atorgant característiques úniques al neurodesenvolupament humà, i contenen variants genètiques de susceptibilitat per a l’esquizofrènia. Per tal de facilitar l’identificar els mecanismes genètics i biològics implicats en l’etiologia de l’esquizofrènia, la utilització de fenotips cerebrals intermedis, com mesures de neuroimatge funcional i estructural, representa una estratègia molt útil. Seguint dues aproximacions centrades en l’anàlisi dels correlats genètics-fenotípics entre gens candidats relacionats amb la plasticitat sinàptica i regions HARs i les alteracions cerebrals de l’esquizofrènia, aquesta tesi inclou quatre articles originals i una revisió sistemàtica. En aquests articles, exposem l’efecte de polimorfismes en els gens KCNH2, DISC1, CACNA1C i ZNF804A i la càrrega poligènica en conjunts informatius de HARs sobre les diferències observades entre cervells de persones sanes i persones amb esquizofrènia. En conjunt, els resultats validen l’efectivitat dels fenotips de neuroimatge per identificar els determinants genètics de l’esquizofrènia i posen de manifest la complementarietat de les aproximacions centrades tant en gens candidats com en la variabilitat global del genoma per a l’estudi de l’arquitectura genètica del trastorn. Primer, descrivim el paper de la variabilitat genètica dels genes KCNH2 i DISC1 en la modulació de la resposta funcional a l’atenció i la memòria de treball de manera condicionada al diagnòstic. També, identifiquem que l’epistasi entre dos gens associats amb l’esquizofrènia a nivell de GWAS, el CACNAC1C i el ZNF804A, influeix en la capacitat funcionalde cervell per adaptar-se a l’increment de requeriments cognitius en memòria de treball en controls sans i pacients amb esquizofrènia. En segon lloc, oferim una revisió sobre com les HARs sustenten les característiques del neurodesenvolupament humà, la configuració cerebral, el funcionament i la susceptibilitat per als trastorns psiquiàtrics Així mateix, informem de l'efecte modulador de la poligenicitat de les HARs sobre les diferències en l’arquitectura cortical en l'esquizofrènia i proporcionem evidències sobre l’especial rellevància de les HARs associades amb elements reguladors de la transcripció actius durant l’etapa fetal. De manera global, els resultats d’aquesta tesi indiquen que els fonaments etiològics de l’esquizofrènia estan relacionats amb diferències genètiques individuals que impacten en les trajectòries del neurodesenvolupament i les vies de plasticitat sinàptica, així com amb la composició genòmica que ens defineix com a espècie. Aquesta tesi aporta una gota en l’oceà del coneixement sobre els trastorns intrínsecament vinculats a la condició humana i ha pretès contribuir en la comprensió de les característiques úniques del nostre cervell per ajudar a entendre què vol dir ser humà.[spa] La esquizofrenia es un trastorno psiquiátrico que afecta a 24 millones de personas en todo el mundo. A pesar de que empezamos a conocer los mecanismos biológicos implicados en el origen del trastorno, los procesos etiológicos precisos continúan siendo en gran parte desconocidos. Por ello, los esfuerzos investigadores todavía necesitan dirigirse en mejorar el conocimiento de los fundamentos biológicos del trastorno, para así conseguir una mayor precisión en el diagnóstico y desarrollar nuevas estrategias terapéuticas que mejoren la calidad de vida de los pacientes. La hipótesis etiopatogénica predominante considera que el trastorno se origina de la interacción entre factores genéticos y ambientales que modifican los mecanismos perfectamente orquestados que guían el neurodesarrollo. Además, desde una perspectiva evolutiva, se sostiene que la esquizofrenia representa “el precio a pagar” por la evolución de los procesos ontogénicos específicamente humanos que sustentan la complejidad y la variabilidad inherente al funcionamiento del cerebro, así como la cognición y comportamiento de nuestra especie. A lo largo del neurodesarrollo, la formación de sinapsis y la organización y maduración de los circuitos neurales anclan la aparición de funciones cerebrales corticales distintivamente humanas. Por su parte, evidencias multidisciplinares indican que las alteraciones sinápticas participan en disfunciones cerebrales asociadas a la aparición de los síntomas cognitivos y clínicos de la esquizofrenia. En consecuencia, se ha propuesto que las alteraciones de la plasticidad sináptica tienen un papel crítico en la fisiopatología del trastorno. Entre los genes que confluyen en vías del neurodesarrollo y de plasticidad sináptica, hay genes que participan en vías de señalización implicadas en la homeostasis neuronal, el desarrollo de las espinas dendríticas y la excitabilidad neural, como el KCNH2, el DISC1, el CACNA1C y el ZNF804A, todos ellos previamente asociados con el riesgo para la esquizofrenia. Además, aproximaciones evolutivas han identificado regiones que han acumulado cambios específicamente humanos desde la divergencia con los chimpancés, como las Regiones Humanas Aceleradas (o Human Accelerated Regions, HARs en inglés). Estas regiones actúan como elementos reguladores de la transcripción otorgando características únicas al neurodesarrollo humano, y albergan variantes genéticas de susceptibilidad para la esquizofrenia. Para facilitar la identificación de los mecanismo genéticos y biológicos implicados en la etiología del trastorno, el uso de fenotipos cerebrales intermedios, como medidas de neuroimagen funcional y estructural, es una herramienta de gran valor. Siguiendo dos aproximaciones centradas en el análisis de los correlatos genético- fenotípicos entre genes candidatos relacionados con la plasticidad sináptica y secuencias HARs y las alteraciones cerebrales en la esquizofrenia, esta tesis incluye cuatro artículos originales y una revisión sistemática. En estos artículos, exponemos el efecto de polimorfismos en los genes KCNH2, DISC1, CACNA1C y ZNF804A y la carga poligénica en conjuntos informativos de HARs sobre las diferencias observadas entre cerebros sanos y cerebros con esquizofrenia. En su conjunto, los resultados validan la efectividad de los fenotipos de neuroimagen para identificar los mecanismos genéticos de la esquizofrenia y ponen de manifiesto la complementariedad de las aproximaciones centradas tanto en genes candidatos como en la variabilidad global del genoma para estudiar la arquitectura genética del trastorno. Primero describimos el papel de la variabilidad genética de los genes KCNH2 y DISC1 en la modulación de la respuesta funcional a la atención y la memoria de trabajo de manera condicional al diagnóstico. Además, identificamos que la epistasis entre dos genes asociados con la esquizofrenia a nivel de GWAS, el CACNAC1C y el ZNF804A, influye en la capacidad funcional de cerebro para adaptarse al incremento de requerimientos cognitivos en memoria de trabajo tanto en controles sanos como en pacientes con esquizofrenia. En segundo lugar, ofrecemos una revisión sobre cómo las HARs sustentan las características del neurodesarrollo humano, la configuración y el funcionamiento cerebral y la susceptibilidad para trastornos psiquiátricos. Así mismo, informamos del efecto modulador de la poligenicidad de las HARs sobre las diferencias en la arquitectura cortical en la esquizofrenia y proporcionamos evidencias sobre la especial relevancia de las HARs asociadas con elementos reguladores de la transcripción activos durante la etapa fetal. De manera global, los resultados de esta tesis indican que los fundamentos etiológicos de la esquizofrenia están relacionados con diferencias genéticas individuales que impactan en las trayectorias del neurodesarrollo y en las vías de plasticidad sináptica, así como en la composición genética que nos define como especie. Esta tesis aporta una gota en el océano del conocimiento sobre los trastornos intrínsicamente vinculados a la condición humana y ha pretendido contribuir en la comprensión de las características únicas de nuestro cerebro para ayudar a entender qué quiere decir ser humano

    Brain organoids as innovative tool for regenerative medicine

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    The introduction of the tridimensional (3D) organoids technology is revolutionizing the fields of developmental and stem cell biology and it is emerging as the latest frontier in regenerative medicine for the treatment of neurodegenerative disorders, such as epilepsy. The overall objective of my PhD thesis was to set the stage to develop functional hippocampal brain organoid that can be used for regenerative medicine to cure the Temporal Lobe epilepsy (TLE)

    Affective, Interpersonal, and Subjective Aspects of Denial in Anosognosia for Hemiplegia: Neuroscientific and Psychoanalytic Perspectives

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    Some patients customarily deny left hand hemiplegia as a consequence of a right hemispheric stroke. Denial is a key aspect in Anosognosia for Hemiplegia, and is also an essential concept in the development and structure of psychoanalytic theory. In research on AHP, denial is approached from neuroscientific perspectives, which include empirical research on several aspects that are relevant in the presentation of the syndrome (e.g. senso-perception, cognition, neuroanatomy, etc.). Psychoanalysis has emphasised intrapsychic, developmental, and defensive aspects based upon clinical observation of mainly non-neurological patients. However, the Cognitive Arrest Hypothesis (a model stemming from psychoanalytic theory) has proposed a view of denial that is in accordance with, or does not contradict empirical evidence on AHP. Both fields have recognised the importance of affective, motivational, interpersonal, and subjective aspects in the presentation of denial. The Cognitive Arrest Hypothesis allows discussing evidences on denial in AHP research, and in psychoanalytic theory, under a common framework of reference. The present thesis aims at opening a debate between these two fields with the goal of demonstrating how can their arguments be of mutual assistance in further comprehending denial. Three research proposals are presented to illustrate practical ways to consider contributions from both fields in future research and clinical directions

    When smaller is more – investigating the interplay between continuous sensory cues and numerical information

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    Research on numerical cognition is not limited to symbolic numbers and mathematics but it also includes discrete and continuous magnitudes. Continuous magnitudes are ubiquitous in nature and serve as important cues in everyday life situations. When one tries to choose the plate with more cookies in the cafeteria, they usually do not count the cookies but rather arrive at a fair estimate by comparing such continuous magnitudes. For example, nine cookies on a plate will occupy a larger area and have to be placed denser to each other than five cookies. Recent research has shown that, as opposed to the classical view, the processing of symbolic numbers and non-symbolic numerosities is not independent from such sensory cues. The present dissertation consists of two studies that investigate what psychological processes underlie the interaction between sensory cues and numerical information. Study 1 aimed to replicate and extend the findings of Gebuis & Reynvoet who systematically manipulated the relationship between continuous and discrete magnitudes in a non-symbolic numerical comparison task. The main goal was to assess the stability and the robustness of the influence of sensory cues on numerical comparisons as the originally reported patterns suggest a complex interaction between these two kinds of information that are difficult to reconcile with the classic views on numerical processing. Indeed, the results confirmed that continuous magnitudes have a complex effect on numerical judgements and that their interaction can be either due to incomplete inhibition or due to integration of continuous magnitudes during numerical tasks. Study 2 turned to symbolic numbers and investigated whether inhibition underlies the interaction of continuous sensory properties and numerical information. To this end a novel paradigm was introduced that allowed to investigate well-established electrophysiological correlates of inhibition with numerical stimuli. The results provide evidence that inhibition underlies the interaction between sensory cues and numerical information. Additionally, they show that the paradigm introduced in Study 2 may suitable to investigate these processes across different developmental stages and numeracy levels
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