Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation

While experience unfolds continuously, memories are organized as a set of discrete events that bind together the “where”, “when”, and “what” of episodic memory. This segmentation of continuous experience is thought to be facilitated by the detection of salient environmental or cognitive events. However, the underlying neural mechanisms and how such segmentation shapes episodic memory representations remain unclear. We recorded from single neurons in the human medial temporal lobe while subjects watched videos with different types of embedded boundaries and were subsequently evaluated for memories of the video contents. Here we show neurons that signal the presence of cognitive boundaries between subevents from the same episode and neurons that detect the abstract separation between different episodes. The firing rate and spike timing of these boundary-responsive neurons were predictive of later memory retrieval accuracy. At the population level, abrupt neural state changes following boundaries predicted enhanced memory strength but impaired order memory, capturing the behavioral tradeoff subjects exhibited when recalling episodic content versus temporal order. Successful retrieval was associated with reinstatement of the neural state present following boundaries, indicating that boundaries structure memory search. These findings reveal a neuronal substrate for detecting cognitive boundaries and show that cognitive boundary signals facilitate the mnemonic organization of continuous experience as a set of discrete episodic events

Action boosts episodic memory encoding in humans via engagement of a noradrenergic system

We are constantly interacting with our environment whilst we encode memories. However, how actions influence memory formation remains poorly understood. Goal-directed movement engages the locus coeruleus (LC), the main source of noradrenaline in the brain. Noradrenaline is also known to enhance episodic encoding, suggesting that action could improve memory via LC engagement. Here we demonstrate, across seven experiments, that action (Go-response) enhances episodic encoding for stimuli unrelated to the action itself, compared to action inhibition (NoGo). Functional magnetic resonance imaging, and pupil diameter as a proxy measure for LC-noradrenaline transmission, indicate increased encodingrelated LC activity during action. A final experiment, replicated in two independent samples, confirmed a novel prediction derived from these data that emotionally aversive stimuli, which recruit the noradrenergic system, modulate the mnemonic advantage conferred by Go-responses relative to neutral stimuli. We therefore provide converging evidence that action boosts episodic memory encoding via a noradrenergic mechanism

Aversive memory formation in humans involves an amygdala-hippocampus phase code

Memory for aversive events is central to survival but can become maladaptive in psychiatric disorders. Memory enhancement for emotional events is thought to depend on amygdala modulation of hippocampal activity. However, the neural dynamics of amygdala-hippocampal communication during emotional memory encoding remain unknown. Using simultaneous intracranial recordings from both structures in human patients, here we show that successful emotional memory encoding depends on the amygdala theta phase to which hippocampal gamma activity and neuronal firing couple. The phase difference between subsequently remembered vs. not-remembered emotional stimuli translates to a time period that enables lagged coherence between amygdala and downstream hippocampal gamma. These results reveal a mechanism whereby amygdala theta phase coordinates transient amygdala -hippocampal gamma coherence to facilitate aversive memory encoding. Pacing of lagged gamma coherence via amygdala theta phase may represent a general mechanism through which the amygdala relays emotional content to distant brain regions to modulate other aspects of cognition, such as attention and decision-making

Modeling Fire Danger in Galicia and Asturias (Spain) from MODIS images

Forest fires are one of the most dangerous natural hazards, especially when they are recurrent. In areas such as Galicia (Spain), forest fires are frequent and devastating. The development of fire risk models becomes a very important prevention task for these regions. Vegetation and moisture indices can be used to monitor vegetation status; however, the different indices may perform differently depending on the vegetation species. Eight different spectral indices were selected to determine the most appropriate index in Galicia. This study was extended to the adjacent region of Asturias. Six years of MODIS (Moderate Resolution Imaging Spectroradiometer) images, together with ground fire data in a 10 × 10 km grid basis were used. The percentage of fire events met the variations suffered by some of the spectral indices, following a linear regression in both Galicia and Asturias. The Enhanced Vegetation Index (EVI) was the index leading to the best results. Based on these results, a simple fire danger model was established, using logistic regression, by combining the EVI variation with other variables, such as fire history in each cell and period of the year. A seventy percent overall concordance was obtained between estimated and observed fire frequency

Markov Influence Diagrams.

Markov influence diagrams (MIDs) are a new type of probabilistic graphical model that extends influence diagrams in the same way that Markov decision trees extend decision trees. They have been designed to build state-transition models, mainly in medicine, and perform cost-effectiveness analyses. Using a causal graph that may contain several variables per cycle, MIDs can model various patient characteristics without multiplying the number of states; in particular, they can represent the history of the patient without using tunnel states. OpenMarkov, an open-source tool, allows the decision analyst to build and evaluate MIDs-including cost-effectiveness analysis and several types of deterministic and probabilistic sensitivity analysis-with a graphical user interface, without writing any code. This way, MIDs can be used to easily build and evaluate complex models whose implementation as spreadsheets or decision trees would be cumbersome or unfeasible in practice. Furthermore, many problems that previously required discrete event simulation can be solved with MIDs; i.e., within the paradigm of state-transition models, in which many health economists feel more comfortable

Contribution of the Microbial Communities Detected on an Oil Painting on Canvas to Its Biodeterioration

In this study, we investigated the microbial community (bacteria and fungi) colonising an oil painting on canvas, which showed visible signs of biodeterioration. A combined strategy, comprising culture-dependent and -independent techniques, was selected. The results derived from the two techniques were disparate. Most of the isolated bacterial strains belonged to related species of the phylum Firmicutes, as Bacillus sp. and Paenisporosarcina sp., whereas the majority of the non-cultivable members of the bacterial community were shown to be related to species of the phylum Proteobacteria, as Stenotrophomonas sp. Fungal communities also showed discrepancies: the isolated fungal strains belonged to different genera of the order Eurotiales, as Penicillium and Eurotium, and the non-cultivable belonged to species of the order Pleosporales and Saccharomycetales. The cultivable microorganisms, which exhibited enzymatic activities related to the deterioration processes, were selected to evaluate their biodeteriorative potential on canvas paintings; namely Arthrobacter sp. as the representative bacterium and Penicillium sp. as the representative fungus. With this aim, a sample taken from the painting studied in this work was examined to determine the stratigraphic sequence of its cross-section. From this information, “mock paintings,” simulating the structure of the original painting, were prepared, inoculated with the selected bacterial and fungal strains, and subsequently examined by micro-Fourier Transform Infrared spectroscopy, in order to determine their potential susceptibility to microbial degradation. The FTIR-spectra revealed that neither Arthrobacter sp. nor Penicillium sp. alone, were able to induce chemical changes on the various materials used to prepare “mock paintings.” Only when inoculated together, could a synergistic effect on the FTIR-spectra be observed, in the form of a variation in band position on the spectrum.The FTIR analyses performed in this study were financed by the Junta de Andalucía (RNM-325 group). The molecular analyses performed in this study were financed by the Austrian Science Fund (FWF) project ‘Hertha-Firnberg T137’ and the Spanish Ministry of Science and Innovation (Project CTQ2008-06727-C03-03). G. Piñar also thanks the “Elise-Richter V194-B20” projects

How can we process microelectrode data to isolate single neurons in humans?

Extracellular recordings of single neurons are a commonly used method to study the neural mechanisms of cognition. While extensively used in animal models, rare clinical cases also allow such recordings from the human brain using high-impedance microwires. These recordings allow the study of the activity of individual human neurons during cognitive tasks at single-spike resolution. Here, we discuss one such clinical scenario: microwires embedded in depth electrodes implanted in epilepsy patients. We outline the three main processing steps to derive well isolated putative single neurons from such recordings: signal processing, spike detection, and spike sorting. We provide an overview of the state of the art in the acquisition and processing of extracellular recordings with microwires, review a typical experimental setup, spike sorting and detection algorithms. We conclude by providing a step-by-step example, visualizing each intermediate processing step. Together, this chapter provides a practical guide on how to utilize signal processing, spike detection, and spike sorting to derive high-quality single-neuron recordings

Mechanisms underlying memory enhancement in humans

La memoria ha sido objeto de investigación desde 1800. A día de hoy sabemos que existen diversos factores que modulan la memoria como emociones, eventos inesperados y relaciones semánticas; pero aún se desconocen los mecanismos neurales subyacentes en humanos. En esta tesis se exploran las bases neurales de dos factores que influyen en la memoria: acción y novedad. El movimiento voluntario no ha sido tradicionalmente considerado como un factor que aumenta la memoria. Sin embargo, los primeros indicios de una posible relación entre memoria y movimiento voluntario provienen de estudios a finales de los años 60 en los que se observó cómo lesiones en la estructura fundamental de memoria en el cerebro, el hipocampo, provocaban hiperactividad en roedores. Más tarde, otros estudios han confirmado esta relación entre ejecución de movimientos voluntarios y actividad hipocampal en humanos, pero desde entonces hasta ahora poco se conoce a cerca de una posible relación entre los sistemas motor y de memoria más allá de que una representación activa de aquello que codificamos facilita su posterior recuerdo. En esta tesis se estudia la hipótesis de que movimientos voluntarios que se ejecutan a la vez que se codifica una información visual, completamente no relacionada con el movimiento realizado, influyen en su posterior recuerdo. Esta tesis da respuesta a esta pregunta, mediante una serie de experimentos conductuales, demostrando que el hecho de realizar un movimiento voluntario aumenta la memoria de aquello que codificamos simultáneamente. Mediante técnicas de Resonancia Magnética Funcional y pupilometría se demuestra que este efecto es mediado por el sistema noradrenérgico. Además conectividad funcional entre el Locus Cerúleo –fuente fundamental de noradrenalina en el cerebro- y el giro parahipocampal –región que ejerce un rol importante en la codificación de memoria episódica- ha sido observado. Estos hallazgos implican que el hecho de realizar un movimiento voluntario podría provocar la liberación de noradrenalina en el Locus Cerúleo, que al llegar a áreas de memoria como el giro hipocampal, favorece el recuerdo de aquello que codificamos simultáneamente. Otro factor que facilita la memoria es la novedad o lo inesperado, en definitiva, aquello que produce una discordancia entre aquello que esperamos (en base a predicciones basadas en el pasado) y aquello que en realidad ocurre. Lesiones en el hipocampo humano afectan la adquisición de nuevas memorias, lo que sugiere un posible rol de esta estructura en el procesamiento de estímulos novedosos. La respuesta del hipocampo a este tipo de estímulos ha sido estudiada en animales y en humanos mediante técnicas de neuroimagen funcional y neurofisiológicas pero poco se conoce aún acerca de los mecanismos neurales subyacentes que el hipocampo utiliza para responder ante la experiencia de algo novedoso. Por otro lado, el hipocampo se encuentra en el Lóbulo Temporal Medial y posee una estructura alargada. Se conocen diferencias anatómicas, funcionales, de conectividad e incluso a nivel de expresión genética de esta estructura a lo largo del eje longitudinal. Se ha demostrado en roedores un rol funcional de la frecuencia oscilatoria en la banda theta que decrece de partes dorsales a partes ventrales del hipocampo a la vez que se observa un aumento el tamaño de la región de espacio en la que se activan las células de lugar. Una evaluación sistemática de las frecuencias gamma y theta a lo largo del eje longitudinal del hipocampo no ha sido descrita todavía en humanos. En esta tesis se ha estudiado la respuesta electrofisiológica mediante el análisis de registros intracraneales profundos -electroencefalografía intracraneal (iEEG)- en pacientes epilépticos resistentes a tratamiento farmacológico; para caracterizar la respuesta de diferentes porciones del hipocampo (cabeza, cuerpo y cola) ante estímulos novedosos. Una inversión de polaridad observada en los potenciales evocados entre la cabeza y la cola, nos llevan a sugerir la existencia de una posible fuente eléctrica para actividad evocada por novedad en la porción anterior del hipocampo. A nivel electrofisiológico diferentes porciones del hipocampo experimentan un incremento en su actividad en las bandas frecuenciales theta y gamma, reflejando posiblemente un incremento en la actividad local de cada porción longitudinal. Análisis de coherencia y seguimiento de fase revelan que diferentes porciones del hipocampo están sincronizadas de manera similar. A pesar de que un aumento de coherencia en la banda theta entre diferentes regiones del hipocampo durante el procesamiento de novedad ha sido observado, no se han encontrado dichas diferencias en los valores de sincronización de fase. Esta sincronización y consistencia de fase observada entre diferentes porciones del hipocampo nos llevaron a estudiar un patrón oscilatorio, observado previamente en roedores y en un número limitado de pacientes humanos, que muestra cómo oscilaciones en la banda theta viajan a lo largo del eje longitudinal del hipocampo (de partes posteriores a partes anteriores) denominado “ondas viajeras”. Esta tesis confirma la existencia ondas, no solo en la banda theta, sino también en la banda alpha; viajando a lo largo del eje longitudinal del hipocampo de partes posteriores a partes anteriores. Esto implica que diferentes porciones del hipocampo experimentan diferentes fases al mismo tiempo, lo que podría representar un potencial mecanismo para la codificación de información. No se ha encontrado ninguna diferencia a lo largo del eje longitudinal en el acoplamiento entre bajas frecuencias y gamma. A pesar de las diferencias conocidas a lo largo del eje longitudinal junto con estudios anteriores que sugieren una disociación funcional entre porciones anteriores y posteriores del hipocampo en el procesamiento de la novedad, esta tesis sugiere propiedades comunes en la respuesta oscilatoria a lo largo del eje longitudinal. Diferentes enfoques y modalidades han sido utilizados en esta tesis para estudiar diferentes factores que modulan la memoria en humanos. Esta tesis demuestra por primera vez que movimientos voluntarios aumentan la memoria de aquello que codificamos simultáneamente a través de un mecanismo noradrenérgico en humanos. Por otro lado una evaluación comprensiva de la respuesta neurofisiológica del hipocampo ante la novelad en humanos ha sido presentada, con énfasis en aspectos comunes entre diferentes frecuencias y diferencias en las propiedades de la respuesta a lo largo del eje longitudinal del hipocampo. ABSTRACT Memory has been a focus of intensive research since the 1800s. Currently, we know of several factors that modulate episodic memory, such as emotions, reward, unexpected events and semantic relations. However the mechanisms underlying this modulation remain unknown in humans. This thesis explores the neural bases of two factors which influence memory –actions and unexpectedness. Movement is not typically considered a factor that modulates memory but in the 1960s a possible relationship between movement and memory was suggested by evidence that lesions of the hippocampus–a region with a key role in episodic memory- provoked hyperactivity in rodents. Later studies in humans have confirmed a relationship between voluntary movement and hippocampal activity, but little is currently known about the relationship between motor and memory systems. In this thesis the hypothesis that voluntary movements, completely unrelated with the memory content, influence episodic memory is tested in humans. Across a series of behavioral experiments, a voluntary movement-evoked episodic memory enhancement was found. Furthermore, fMRI and pupilometry analysis revealed that this memory enhancement is mediated by the noradrenergic system. In addition, functional connectivity was observed between the Locus Coeruleus –the main source of noradrenaline in the brain-, and the parahippocampal gyrus –a region known to represent an important role in episodic memory encoding. This implies that a voluntary movement triggers the release of noradrenaline in the brain that targets memory areas to promote episodic memory encoding. Another factor known to modulate episodic memory is novelty, which can be defined as any event that represents a mismatch between expectation and experience. Hippocampal damage impairs the acquisition of novel episodic memories, which may suggest a role in processing novel stimuli. Hippocampal responses to novelty stimuli has been studied in animals and humans with different functional neuroimaging and electrophysiological techniques, however differences in the novelty processing along the long axis of the hippocampus remain unknown. Anatomical, functional, connectivity and genetic differences have been shown along the long axis of the hippocampus. A functional role of theta oscillatory frequency has been ascribed along the longitudinal axis in rodents decreasing from dorsal to ventral portions in rodents concomitant with an increase in place field size. A systematic evaluation of gamma and theta frequencies along the longitudinal axis has not been done in humans. In this thesis electrophysiological correlates with novelty have been studied along the longitudinal axis of the human hippocampus in pharmaco-resistant epileptic patients using intracranial electroencephalography (iEEG) recordings. A polarity inversion of the event related potential between the head and the body observed, lead us to suggest a possible electrical novelty-evoked source within the anterior portion of the hippocampus. Different portions of the hippocampus (head, body and tail) show a within-region power increase in theta and gamma frequency bands, reflecting increased local activity in each longitudinal portion during novelty processing. Analysis of phase locking value and imaginary coherence revealed between-region theta coherence increase. However, phase locking values were not affected by unexpectancy indicating that different portions of the hippocampus were similarly synchronized. This consistent phase relationship in theta between portions of the hippocampus led us to test for the presence of traveling waves along the hippocampal long-axis (as has been recently shown in rodents and in limited number of human patients). We confirmed theta (and alpha) traveling wave pattern along the long axis of the hippocampus from posterior to anterior segments. This implies that the hippocampus experiences different phases of theta and alpha frequencies at the same time, potentially representing a mechanism for coding information. No differences on the lower frequencies modulating the gamma envelope during novelty processing across the long-axis were observed. Despite known differences along the long axis of the hippocampus and previous studies showing a functional segregation in novelty processing between anterior and posterior hippocampal portions, results in this thesis suggest common oscillatory response properties across the long-axis. Different approaches have been used in this thesis to study different factors that modulate episodic memory in humans: actions and novelty. The first demonstration of voluntary movement-evoked modulation of memory for stimuli unrelated to the action is described, as well as a mechanistic account for this effect mediated by noradrenergic system. Next, a comprehensive evaluation of the electrophysiological response to novelty in human hippocampus is presented, with focus on commonalities and differences in response properties along the different portions of the hippocampal long axis