3,153 research outputs found

    Towards Neuromorphic Gradient Descent: Exact Gradients and Low-Variance Online Estimates for Spiking Neural Networks

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    Spiking Neural Networks (SNNs) are biologically-plausible models that can run on low-powered non-Von Neumann neuromorphic hardware, positioning them as promising alternatives to conventional Deep Neural Networks (DNNs) for energy-efficient edge computing and robotics. Over the past few years, the Gradient Descent (GD) and Error Backpropagation (BP) algorithms used in DNNs have inspired various training methods for SNNs. However, the non-local and the reverse nature of BP, combined with the inherent non-differentiability of spikes, represent fundamental obstacles to computing gradients with SNNs directly on neuromorphic hardware. Therefore, novel approaches are required to overcome the limitations of GD and BP and enable online gradient computation on neuromorphic hardware. In this thesis, I address the limitations of GD and BP with SNNs by proposing three algorithms. First, I extend a recent method that computes exact gradients with temporally-coded SNNs by relaxing the firing constraint of temporal coding and allowing multiple spikes per neuron. My proposed method generalizes the computation of exact gradients with SNNs and enhances the tradeoffs between performance and various other aspects of spiking neurons. Next, I introduce a novel alternative to BP that computes low-variance gradient estimates in a local and online manner. Compared to other alternatives to BP, the proposed method demonstrates an improved convergence rate and increased performance with DNNs. Finally, I combine these two methods and propose an algorithm that estimates gradients with SNNs in a manner that is compatible with the constraints of neuromorphic hardware. My empirical results demonstrate the effectiveness of the resulting algorithm in training SNNs without performing BP

    Circadian distribution of epileptiform discharges in epilepsy: Candidate mechanisms of variability

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    This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: All code used to produce the results presented in this manuscript are available on GitHub at https://github.com/imarinelli/Marinelli_PLOSCB2022Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy-so-called interictal epileptiform activity-with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.University of Birmingham Dynamic Investment FundEpilepsy Research UKEngineering and Physical Sciences Research Council (EPSRC)National Institute for Health and Care Research (NIHR)Medical Research Council (MRC

    NeuroGame: neural mechanisms underlying cognitive improvement in video gamers

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    The video game market represents an influential and profitable industry. But concerns have been raised how video games impact on the human mind. There are reservations that video gaming may be addictive and foster aggressive behaviour. In contrast, a convincing body of research indicates that playing video games may improve cognitive processing. The exact mechanism thereof is not entirely understood. Most research suggests that video games train individuals in learning how to employ attentional control to focus on processing relevant information, while being able to suppress irrelevant information. Thus, video game players acquire the ability of being able to develop strategies to process information more efficiently. However, no algorithmic solution therefore has been provided yet. Thus, it is not clear which and how attentional control functions contribute to these effects. Moreover, neural mechanisms thereof are not well understood. We hypothesized that alterations in alpha power, i.e., modulations in brain oscillatory activity around 10 Hz, represent a promising neural substrate of video gaming effects. This was because, alpha activity represents an established neural correlate of attention processing given that its amplitude modulation corresponds to alterations in information processing. We investigated this by relating differential cognitive processing in video game players to changes in alpha power modulation. Moreover, we tried to imitate this effect using non-invasive brain stimulation. We were successful in achieving the former but not the latter. We provide a reasonable explanation for this. Thus, our results mostly support our hypothesis according to which altered alpha power may account for gaming effects

    The influence of morphometric changes of gray and white matter on brain functional connectivity in schizophrenia

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    Více než století po vymezení konceptu schizofrenie (SZ) zůstává její etiologie, neuropatologie a patofyziologie do značné míry neobjasněná. Teoretická část práce přináší přehled současných znalostí o klasifikaci a patofyziologii SZ se zvláštním zřetelem věnovaným strukturálním a funkčně zobrazovácím metodám. Zobrazovací nálezy se shodují na tom, že u SZ dochází k redukci šedé hmoty, poruše integrity bílé hmoty a snížení inter-regionální funkční konektivity (FC). Otevřenou otázkou zůstává, zda jsou změny FC od počátku spojené se strukturálními změnami mozku (které jsou jednoznačně potvrzené již před propuknutím nemoci), nebo zda se vyvíjí až s chronifikací SZ. Současně není jasná souvislost mezi narušením FC a prožitkem "jáství", jako možnou jádrovou symptomatikou SZ. Rovněž je nebytné vyvíjet efektivní metody prevence relapsu s cílem zabránit progresi neurobiologických změn mozku. V návaznosti na uvedené otázky zahrnovala praktická část práce celkem tři cíle, v rámci kterých jsme studovali tři odlišné skupiny nemocných. V první skupině pacientů po první epizodě schizofrenie (FES) jsme hodnotili souvislost mezi morfologickými změnami šedé a bílé hmoty mozku a funkční konektivitou. V téže populaci jsme pak studovali změny regionální mozkové konektivity v kontextu narušeného prožitkem "jáství". Druhá...More than a century has passed since a clear definition for schizophrenia was established, yet, the etiology, neuropathological and pathophysiological mechanisms of this psychiatric disorder still, to a large extent, remain to be elucidated. In the theoretical part of this dissertation, we review current classification and pathophysiology of schizophrenia, paying a particular attention to the findings from structural and functional imaging techniques. These techniques demonstrate that patients with schizophrenia tend to have reduced volume of grey matter, reduced integrity of white matter and a disrupted inter-regional functional connectivity (FC). The temporal association between structural changes, already detectable on imaging before symptoms appear, and development of disrupted FC remains to be uncovered. At the same time, current knowledge does not fully explain the link between disrupted FC and disturbed experience of self-awareness, a core symptom of schizophrenia. In addition, it is necessary to develop novel effective methods to prevent relapse and prevent the progression of neurobiological changes in the brain. In the practical part of this dissertation, we designed a study with three different groups of subjects aiming to fulfil three key aims that would help us to fill the gaps in...Klinika psychiatrie a lékařské psychologie 3. LF UK a NÚDZDepartment of Psychiatry and Medical Psychology 3FM CU and NIMH3. lékařská fakultaThird Faculty of Medicin

    Hippocampal neurons code individual episodic memories in humans

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    The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode

    Oscillatory mechanisms of conscious perception and attention

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    Although the prominent role of neural oscillations in perception and cognition has been continuously investigated, some critical questions remain unanswered. My PhD thesis was aimed at addressing some of them. First, can we dissociate oscillatory underpinnings of perceptual accuracy and subjective awareness? Current work would strongly suggest that this dissociation can be drawn. While the fluctuations in alpha-amplitude decide perceptual bias and metacognitive abilities, the speed of alpha activity (i.e., alpha-frequency) dictates sensory sampling, shaping perceptual accuracy. Second, how are these oscillatory mechanisms integrated during attention? The obtained results indicate that a top-down visuospatial mechanism modulates neural assemblies in visual areas via oscillatory re-alignment and coherence in the alpha/beta range within the fronto-parietal brain network. These perceptual predictions are reflected in the retinotopically distributed posterior alpha-amplitude, while perceptual accuracy is explained by the higher alpha-frequency at the to-be-attended location. Finally, sensory input, elaborated via fast gamma oscillations, is linked to specific phases of this slower activity via oscillatory nesting, enabling integration of the feedback-modulated oscillatory activity with sensory information. Third, how can we relate this oscillatory activity to other neural markers of behaviour (i.e., event-related potentials)? The obtained results favour the oscillatory model of ERP genesis, where alpha-frequency shapes the latency of early evoked-potentials, namely P1, with both neural indices being related to perceptual accuracy. On the other hand, alpha-amplitude dictates the amplitude of later P3 evoked-response, whereas both indices shape subjective awareness. Crucially, by combining different methodological approaches, including neurostimulation (TMS) and neuroimaging (EEG), current work identified these oscillatory-behavior links as causal and not just as co-occurring events. Current work aimed at ameliorating the use of the TMS-EEG approach by explaining inter-individual differences in the stimulation outcomes, which could be proven crucial in the way we design entrainment experiments and interpret the results in both research and clinical settings

    Microcircuit structures of inhibitory connectivity in the rat parahippocampal gyrus

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    Komplexe Berechnungen im Gehirn werden durch das Zusammenspiel von exzitatorischen und hemmenden Neuronen in lokalen Netzwerken ermöglicht. In kortikalen Netzwerken, wird davon ausgegangen, dass hemmende Neurone, besonders Parvalbumin positive Korbzellen, ein „blanket of inhibition” generieren. Dieser Sichtpunkt wurde vor kurzem durch Befunde strukturierter Inhibition infrage gestellt, jedoch ist die Organisation solcher Konnektivität noch unklar. In dieser Dissertation, präsentiere ich die Ergebnisse unserer Studie Parvabumin positiver Korbzellen, in Schichten II / III des entorhinalen Kortexes und Präsubiculums der Ratte. Im entorhinalen Kortex haben wir dorsale und ventrale Korbzellen beschrieben und festgestellt, dass diese morphologisch und physiologisch ähnlich, jedoch in ihrer Konnektivität zu Prinzipalzellen dorsal stärker als ventral verbunden sind. Dieser Unterschied korreliert mit Veränderungen der Gitterzellenphysiologie. Ähnlich zeige ich im Präsubiculum, dass inhibitorische Konnektivität eine essenzielle Rolle im lokalen Netzwerk spielt. Hemmung im Präsubiculum ist deutlich spärlicher ist als im entorhinalen Kortex, was ein unterschiedliches Prinzip der Netzwerkorganisation suggeriert. Um diesen Unterschied zu studieren, haben wir Morphologie und Netzwerkeigenschaften Präsubiculärer Korbzellen analysiert. Prinzipalzellen werden über ein vorherrschendes reziprokes Motif gehemmt die durch die polarisierte Struktur der Korbzellaxone ermöglicht wird. Unsere Netzwerksimulationen zeigen, dass eine polarisierte Inhibition Kopfrichtungs-Tuning verbessert. Insgesamt zeigen diese Ergebnisse, dass inhibitorische Konnektivität, funktioneller Anforderungen der lokalen Netzwerke zur Folge, unterschiedlich strukturiert sein kann. Letztlich stelle ich die Hypothese auf, dass für lokale inhibitorische Konnektivität eine Abweichung von „blanket of inhibition― zur „maßgeschneiderten― Inhibition zur Lösung spezifischer computationeller Probleme vorteilhaft sein kann.Local microcircuits in the brain mediate complex computations through the interplay of excitatory and inhibitory neurons. It is generally assumed that fast-spiking parvalbumin basket cells, mediate a non-selective -blanket of inhibition-. This view has been recently challenged by reports structured inhibitory connectivity, but it’s precise organization and relevance remain unresolved. In this thesis, I present the results of our studies examining the properties of fast-spiking parvalbumin basket cells in the superficial medial entorhinal cortex and presubiculum of the rat. Characterizing these interneurons in the dorsal and ventral medial entorhinal cortex, we found basket cells of the two subregions are more likely to be connected to principal cells in the dorsal compared to the ventral region. This difference is correlated with changes in grid physiology. Our findings further indicated that inhibitory connectivity is essential for local computation in the presubiculum. Interestingly though, we found that in this region, local inhibition is lower than in the medial entorhinal cortex, suggesting a different microcircuit organizational principle. To study this difference, we analyzed the properties of fast-spiking basket cells in the presubiculum and found a characteristic spatially organized connectivity principle, facilitated by the polarized axons of the presubicular fast-spiking basket cells. Our network simulations showed that such polarized inhibition can improve head direction tuning of principal cells. Overall, our results show that inhibitory connectivity is differently organized in the medial entorhinal cortex and the presubiculum, likely due to functional requirements of the local microcircuit. As a conclusion to the studies presented in this thesis, I hypothesize that a deviation from the blanket of inhibition, towards a region-specific, tailored inhibition can provide solutions to distinct computational problems

    Passive and active markers of cortical excitability in epilepsy

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    Electroencephalography (EEG) has been the primary diagnostic tool in clinical epilepsy for nearly a century. Its review is performed using qualitative clinical methods that have changed little over time. However, the intersection of higher resolution digital EEG and analytical tools developed in the past decade invites a re-exploration of relevant methodology. In addition to the established spatial and temporal markers of spikes and high-frequency oscillations, novel markers involving advanced postprocessing and active probing of the interictal EEG are gaining ground. This review provides an overview of the EEG-based passive and active markers of cortical excitability in epilepsy and of the techniques developed to facilitate their identification. Several different emerging tools are discussed in the context of specific EEG applications and the barriers we must overcome to translate these tools into clinical practice

    Characterizing of Robo downstream signalling to promote direct neurogenesis

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    The size and degree of folding of the mammalian cortex are pivotal factors that affect species’ cognitive abilities and sensorimotor skills. The cerebral cortex is the main region in the mammalian brain that governs complex cognitive behaviors. The development of the cortex depends on the amplification of neural stem cells (NSCs), neural progenitors (NPs) and the generation and differentiation of postmitotic neurons. There are two main types of NPs in the mouse neocortex (NCx): apical radial glia (aRGCs) and intermediate progenitor cells (IPCs). Robo receptors play an important role in regulating the amplification of cortical progenitors. The absence of Robo receptor signalling plus the alteration of the Notch signalling pathway in the mouse NCx leads to an overproduction of poorly functional IPCs. Ancient amniotic cortices exhibit a predominance of direct neurogenesis during development, where aRGCs produce neurons directly. Intriguingly, Robo receptors as well as Notch signalling play a major role in attenuating the mode of neurogenesis. This hypothesis was validated in several brain structures with phyletic antiquity, confirming that Robo receptors are essential in the shift towards indirect neurogenesis during the evolution and expansion of the cerebral cortex. However, little is known about the precise signalling cascade or interactors employed by Robo to initiate direct neurogenesis. In this thesis, we demonstrated the transcriptomic differences between the developing mouse NCx and OB (where direct neurogenesis is predominant in the OB vs NCx) using single cell RNA sequencing (scRNA). We showed aRGCs populations that are differently enriched between these regions. We traced lineage trajectories of indirect and direct neurogenesis, as well as validating the expression of several differentially expressed genes between the two regions. We used Robo intracellular domain (ICD)—this region is considered a constitutively active form of Robo receptor—and demonstrated the protein interactors that bind it. Following that, we demonstrated Robo ICD localization to the nucleus. We discovered that Robo conserved cytoplasmic domains play an important role in Robo ICD nucleocytoplasmic localization and direct neurogenesis induction in the mouse NCx. Next, we showed that Robo ICD localizes to chromatin, and causes transcriptional changes that occur upon the experimental gain of function of Robo ICD in the NCx and in vitro. Additionally, we showed that loss of function of Nup107, a nuclear pore complex (NPC) protein and one of Robo ICD protein interactors, induces direct neurogenesis in mouse NCx and chick lateral pallium. Taken together, our findings suggest the transcriptional role Robo ICD exerts by binding DNA and, consequently, its conserved role in moderating direct neurogenesis. El tamaño y el grado de plegamiento de la corteza cerebral son factores fundamentales que afectan a las capacidades cognitivas y habilidades sensoriomotoras de los mamíferos. La corteza cerebral es la principal región del cerebro que gobierna conductas cognitivas complejas. El desarrollo de la corteza depende de la amplificación de células madre neurales (CMN), progenitores neurales (PN) y de la generación y diferenciación de neuronas postmitóticas. Hay dos tipos principales de PN en la neocorteza o neocórtex (NCx) del ratón: las células de glía radial apical (CGRa) y las células progenitoras intermedias (CPI). Los receptores Robo juegan un papel importante en la regulación de la amplificación de los progenitores corticales. La ausencia de señalización del receptor Robo sumada a la alteración de la vía de señalización de Notch en el NCx de ratón conduce a una sobreproducción de CPI poco funcionales. La corteza de especies amniotas anteriores en la evolución a los mamíferos (como los reptiles y las aves) exhiben un predominio de neurogénesis directa durante el desarrollo, por el cual las CGRa producen neuronas directamente. Curiosamente, los receptores Robo, así como la señalización de Notch, desempeñan un papel importante en la atenuación de esta modalidad de neurogénesis a lo largo de la evolución. Esta hipótesis ha sido validada en varias estructuras cerebrales con antigüedad filética, confirmando que los receptores Robo son esenciales en el cambio hacia la neurogénesis indirecta durante la evolución y la consecuente expansión de la corteza cerebral. Sin embargo, se sabe poco sobre la cascada de señalización de Robo, así como de los mensajeros secundarios empleados por este receptor para iniciar el proceso de neurogénesis directa. En esta tesis, demostramos las diferencias transcriptómicas que existen entre el NCx y el bulbo olfatorio (BO) de ratón en desarrollo (sabiendo que la neurogénesis directa es predominante en BO frente al NCx). Para ello usamos la técnica de secuenciación de ARN de células individuales (single-cell RNA sequencing (scRNAseq) en inglés). Mostramos que hay poblaciones de RGCa que están diferentemente enriquecidas entre estas regiones. Trazamos trayectorias de linaje de neurogénesis indirecta y directa y validamos la expresión de varios genes expresados diferencialmente entre las dos regiones. Utilizamos el dominio intracelular (DIC) de Robo (esta región se considera una forma constitutivamente activa del receptor) y demostramos los mensajeros secundarios que se unen. Después, demostramos la localización del DIC de Robo en el núcleo. Descubrimos que sus dominios citoplasmáticos, muy conservados a lo largo de la evolución, tienen un papel importante en la localización núcleo-citoplasmática del DIC y la inducción directa de neurogénesis en el NCx de ratón. A continuación, mostramos que una vez en el núcleo, el DIC se une a la cromatina y provoca cambios transcripcionales que tienen como resultado una la ganancia de función de Robo tanto en el NCx como in vitro. Además, demostramos que la pérdida de función de Nup107, una proteína que forma parte del complejo del poro nuclear (CPN) además de ser una proteína de interacción del DIC de Robo, induce neurogénesis directa en el NCx de ratón y en el palio lateral de pollo. En conjunto, nuestros resultados sugieren el papel de modulación transcripcional que ejerce el DIC de Robo al unirse al ADN y, en consecuencia, su rol conservado a lo largo de la evolución en la disminución de la neurogénesis directa
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