Shared Proteins and Pathways of Cardiovascular and Cognitive Diseases: Relation to Vascular Cognitive Impairment.

One of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.

What happens in the brain when we die? Deciphering the neurophysiology of the final moments in life.

When do we die and what happens in the brain when we die? The mystery around these questions has engaged mankind for centuries. Despite the challenges to obtain recordings of the dying brain, recent studies have contributed to better understand the processes occurring during the last moments of life. In this review, we summarize the literature on neurophysiological changes around the time of death. Perhaps the only subjective description of death stems from survivors of near-death experiences (NDEs). Hallmarks of NDEs include memory recall, out-of-body experiences, dreaming, and meditative states. We survey the evidence investigating neurophysiological changes of these experiences in healthy subjects and attempt to incorporate this knowledge into the existing literature investigating the dying brain to provide valuations for the neurophysiological footprint and timeline of death. We aim to identify reasons explaining the variations of data between studies investigating this field and provide suggestions to standardize research and reduce data variability.

Quantifying Reinforcement-Learning Agent's Autonomy, Reliance on Memory and Internalisation of the Environment.

Intuitively, the level of autonomy of an agent is related to the degree to which the agent's goals and behaviour are decoupled from the immediate control by the environment. Here, we capitalise on a recent information-theoretic formulation of autonomy and introduce an algorithm for calculating autonomy in a limiting process of time step approaching infinity. We tackle the question of how the autonomy level of an agent changes during training. In particular, in this work, we use the partial information decomposition (PID) framework to monitor the levels of autonomy and environment internalisation of reinforcement-learning (RL) agents. We performed experiments on two environments: a grid world, in which the agent has to collect food, and a repeating-pattern environment, in which the agent has to learn to imitate a sequence of actions by memorising the sequence. PID also allows us to answer how much the agent relies on its internal memory (versus how much it relies on the observations) when transitioning to its next internal state. The experiments show that specific terms of PID strongly correlate with the obtained reward and with the agent's behaviour against perturbations in the observations.

Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain.

The neurophysiological footprint of brain activity after cardiac arrest and during near-death experience (NDE) is not well understood. Although a hypoactive state of brain activity has been assumed, experimental animal studies have shown increased activity after cardiac arrest, particularly in the gamma-band, resulting from hypercapnia prior to and cessation of cerebral blood flow after cardiac arrest. No study has yet investigated this matter in humans. Here, we present continuous electroencephalography (EEG) recording from a dying human brain, obtained from an 87-year-old patient undergoing cardiac arrest after traumatic subdural hematoma. An increase of absolute power in gamma activity in the narrow and broad bands and a decrease in theta power is seen after suppression of bilateral hemispheric responses. After cardiac arrest, delta, beta, alpha and gamma power were decreased but a higher percentage of relative gamma power was observed when compared to the interictal interval. Cross-frequency coupling revealed modulation of left-hemispheric gamma activity by alpha and theta rhythms across all windows, even after cessation of cerebral blood flow. The strongest coupling is observed for narrow- and broad-band gamma activity by the alpha waves during left-sided suppression and after cardiac arrest. Albeit the influence of neuronal injury and swelling, our data provide the first evidence from the dying human brain in a non-experimental, real-life acute care clinical setting and advocate that the human brain may possess the capability to generate coordinated activity during the near-death period.

Information Bottleneck as Optimisation Method for SSVEP-Based BCI.

In this study, the information bottleneck method is proposed as an optimisation method for steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI). The information bottleneck is an information-theoretic optimisation method for solving problems with a trade-off between preserving meaningful information and compression. Its main practical application in machine learning is in representation learning or feature extraction. In this study, we use the information bottleneck to find optimal classification rule for a BCI. This is a novel application for the information bottleneck. This approach is particularly suitable for BCIs since the information bottleneck optimises the amount of information transferred by the BCI. Steady-state visual evoked potential-based BCIs often classify targets using very simple rules like choosing the class corresponding to the largest feature value. We call this classifier the arg max classifier. It is unlikely that this approach is optimal, and in this study, we propose a classification method specifically designed to optimise the performance measure of BCIs. This approach gives an advantage over standard machine learning methods, which aim to optimise different measures. The performance of the proposed algorithm is tested on two publicly available datasets in offline experiments. We use the standard power spectral density analysis (PSDA) and canonical correlation analysis (CCA) feature extraction methods on one dataset and show that the current approach outperforms most of the related studies on this dataset. On the second dataset, we use the task-related component analysis (TRCA) method and demonstrate that the proposed method outperforms the standard argmax classification rule in terms of information transfer rate when using a small number of classes. To our knowledge, this is the first time the information bottleneck is used in the context of SSVEP-based BCIs. The approach is unique in the sense that optimisation is done over the space of classification functions. It potentially improves the performance of BCIs and makes it easier to calibrate the system for different subjects.

Deep neural networks using a single neuron: folded-in-time architecture using feedback-modulated delay loops.

Deep neural networks are among the most widely applied machine learning tools showing outstanding performance in a broad range of tasks. We present a method for folding a deep neural network of arbitrary size into a single neuron with multiple time-delayed feedback loops. This single-neuron deep neural network comprises only a single nonlinearity and appropriately adjusted modulations of the feedback signals. The network states emerge in time as a temporal unfolding of the neuron's dynamics. By adjusting the feedback-modulation within the loops, we adapt the network's connection weights. These connection weights are determined via a back-propagation algorithm, where both the delay-induced and local network connections must be taken into account. Our approach can fully represent standard Deep Neural Networks (DNN), encompasses sparse DNNs, and extends the DNN concept toward dynamical systems implementations. The new method, which we call Folded-in-time DNN (Fit-DNN), exhibits promising performance in a set of benchmark tasks.

Modelling the Impact of Robotics on Infectious Spread Among Healthcare Workers.

The Coronavirus disease 2019 (Covid-19) pandemic has brought the world to a standstill. Healthcare systems are critical to maintain during pandemics, however, providing service to sick patients has posed a hazard to frontline healthcare workers (HCW) and particularly those caring for elderly patients. Various approaches are investigated to improve safety for HCW and patients. One promising avenue is the use of robots. Here, we model infectious spread based on real spatio-temporal precise personal interactions from a geriatric unit and test different scenarios of robotic integration. We find a significant mitigation of contamination rates when robots specifically replace a moderate fraction of high-risk healthcare workers, who have a high number of contacts with patients and other HCW. While the impact of robotic integration is significant across a range of reproductive number R0, the largest effect is seen when R0 is slightly above its critical value. Our analysis suggests that a moderate-sized robotic integration can represent an effective measure to significantly reduce the spread of pathogens with Covid-19 transmission characteristics in a small hospital unit.

Perspective Taking in Deep Reinforcement Learning Agents.

Perspective taking is the ability to take into account what the other agent knows. This skill is not unique to humans as it is also displayed by other animals like chimpanzees. It is an essential ability for social interactions, including efficient cooperation, competition, and communication. Here we present our progress toward building artificial agents with such abilities. We implemented a perspective taking task inspired by experiments done with chimpanzees. We show that agents controlled by artificial neural networks can learn via reinforcement learning to pass simple tests that require some aspects of perspective taking capabilities. We studied whether this ability is more readily learned by agents with information encoded in allocentric or egocentric form for both their visual perception and motor actions. We believe that, in the long run, building artificial agents with perspective taking ability can help us develop artificial intelligence that is more human-like and easier to communicate with.

Identifying task-relevant spectral signatures of perceptual categorization in the human cortex.

Human brain has developed mechanisms to efficiently decode sensory information according to perceptual categories of high prevalence in the environment, such as faces, symbols, objects. Neural activity produced within localized brain networks has been associated with the process that integrates both sensory bottom-up and cognitive top-down information processing. Yet, how specifically the different types and components of neural responses reflect the local networks' selectivity for categorical information processing is still unknown. In this work we train Random Forest classification models to decode eight perceptual categories from broad spectrum of human intracranial signals (4-150 Hz, 100 subjects) obtained during a visual perception task. We then analyze which of the spectral features the algorithm deemed relevant to the perceptual decoding and gain the insights into which parts of the recorded activity are actually characteristic of the visual categorization process in the human brain. We show that network selectivity for a single or multiple categories in sensory and non-sensory cortices is related to specific patterns of power increases and decreases in both low (4-50 Hz) and high (50-150 Hz) frequency bands. By focusing on task-relevant neural activity and separating it into dissociated anatomical and spectrotemporal groups we uncover spectral signatures that characterize neural mechanisms of visual category perception in human brain that have not yet been reported in the literature.

A model for time interval learning in the Purkinje cell.

Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

Mental state space visualization for interactive modeling of personalized BCI control strategies.

OBJECTIVE: Numerous studies in the area of BCI are focused on the search for a better experimental paradigm-a set of mental actions that a user can evoke consistently and a machine can discriminate reliably. Examples of such mental activities are motor imagery, mental computations, etc. We propose a technique that instead allows the user to try different mental actions in the search for the ones that will work best. APPROACH: The system is based on a modification of the self-organizing map (SOM) algorithm and enables interactive communication between the user and the learning system through a visualization of user's mental state space. During the interaction with the system the user converges on the paradigm that is most efficient and intuitive for that particular user. MAIN RESULTS: Results of the two experiments, one allowing muscular activity, another permitting mental activity only, demonstrate soundness of the proposed method and offer preliminary validation of the performance improvement over the traditional closed-loop feedback approach. SIGNIFICANCE: The proposed method allows a user to visually explore their mental state space in real time, opening new opportunities for scientific inquiry. The application of this method to the area of brain-computer interfaces enables more efficient search for the mental states that will allow a user to reliably control a BCI system.

ViraMiner: Deep learning on raw DNA sequences for identifying viral genomes in human samples.

Despite its clinical importance, detection of highly divergent or yet unknown viruses is a major challenge. When human samples are sequenced, conventional alignments classify many assembled contigs as "unknown" since many of the sequences are not similar to known genomes. In this work, we developed ViraMiner, a deep learning-based method to identify viruses in various human biospecimens. ViraMiner contains two branches of Convolutional Neural Networks designed to detect both patterns and pattern-frequencies on raw metagenomics contigs. The training dataset included sequences obtained from 19 metagenomic experiments which were analyzed and labeled by BLAST. The model achieves significantly improved accuracy compared to other machine learning methods for viral genome classification. Using 300 bp contigs ViraMiner achieves 0.923 area under the ROC curve. To our knowledge, this is the first machine learning methodology that can detect the presence of viral sequences among raw metagenomic contigs from diverse human samples. We suggest that the proposed model captures different types of information of genome composition, and can be used as a recommendation system to further investigate sequences labeled as "unknown" by conventional alignment methods. Exploring these highly-divergent viruses, in turn, can enhance our knowledge of infectious causes of diseases.

Efficient neural decoding of self-location with a deep recurrent network.

Place cells in the mammalian hippocampus signal self-location with sparse spatially stable firing fields. Based on observation of place cell activity it is possible to accurately decode an animal's location. The precision of this decoding sets a lower bound for the amount of information that the hippocampal population conveys about the location of the animal. In this work we use a novel recurrent neural network (RNN) decoder to infer the location of freely moving rats from single unit hippocampal recordings. RNNs are biologically plausible models of neural circuits that learn to incorporate relevant temporal context without the need to make complicated assumptions about the use of prior information to predict the current state. When decoding animal position from spike counts in 1D and 2D-environments, we show that the RNN consistently outperforms a standard Bayesian approach with either flat priors or with memory. In addition, we also conducted a set of sensitivity analysis on the RNN decoder to determine which neurons and sections of firing fields were the most influential. We found that the application of RNNs to neural data allowed flexible integration of temporal context, yielding improved accuracy relative to the more commonly used Bayesian approaches and opens new avenues for exploration of the neural code.

Direct information transfer rate optimisation for SSVEP-based BCI.

OBJECTIVE: In this work, a classification method for steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) is proposed. The method is based on information transfer rate (ITR) maximisation. APPROACH: The proposed classification method uses features extracted by traditional SSVEP-based BCI methods and finds optimal discrimination thresholds for each feature to classify the targets. Optimising the thresholds is formalised as a maximisation task of a performance measure of BCIs called information transfer rate. However, instead of the standard method of calculating ITR, which makes certain assumptions about the data, a more general formula is derived to avoid incorrect ITR calculation when the standard assumptions are not met. MAIN RESULTS: The proposed method shows good performance in classifying targets of a BCI, outperforming previously reported results on the same dataset by a factor of 2 in terms of ITR. The highest achieved ITR on the used dataset was 62 bit min-1. SIGNIFICANCE: This approach allows the optimal discrimination thresholds to be automatically calculated and thus eliminates the need for manual parameter selection or performing computationally expensive grid searches. The proposed method also provides a way to reduce false classifications, which is important in real-world applications.

Activations of deep convolutional neural networks are aligned with gamma band activity of human visual cortex.

Recent advances in the field of artificial intelligence have revealed principles about neural processing, in particular about vision. Previous work demonstrated a direct correspondence between the hierarchy of the human visual areas and layers of deep convolutional neural networks (DCNN) trained on visual object recognition. We use DCNN to investigate which frequency bands correlate with feature transformations of increasing complexity along the ventral visual pathway. By capitalizing on intracranial depth recordings from 100 patients we assess the alignment between the DCNN and signals at different frequency bands. We find that gamma activity (30-70 Hz) matches the increasing complexity of visual feature representations in DCNN. These findings show that the activity of the DCNN captures the essential characteristics of biological object recognition not only in space and time, but also in the frequency domain. These results demonstrate the potential that artificial intelligence algorithms have in advancing our understanding of the brain.

Machine Learning for detection of viral sequences in human metagenomic datasets.

BACKGROUND: Detection of highly divergent or yet unknown viruses from metagenomics sequencing datasets is a major bioinformatics challenge. When human samples are sequenced, a large proportion of assembled contigs are classified as "unknown", as conventional methods find no similarity to known sequences. We wished to explore whether machine learning algorithms using Relative Synonymous Codon Usage frequency (RSCU) could improve the detection of viral sequences in metagenomic sequencing data. RESULTS: We trained Random Forest and Artificial Neural Network using metagenomic sequences taxonomically classified into virus and non-virus classes. The algorithms achieved accuracies well beyond chance level, with area under ROC curve 0.79. Two codons (TCG and CGC) were found to have a particularly strong discriminative capacity. CONCLUSION: RSCU-based machine learning techniques applied to metagenomic sequencing data can help identify a large number of putative viral sequences and provide an addition to conventional methods for taxonomic classification.

BROJA-2PID: A Robust Estimator for Bivariate Partial Information Decomposition.

Makkeh, Theis, and Vicente found that Cone Programming model is the most robust to compute the Bertschinger et al. partial information decomposition (BROJA PID) measure. We developed a production-quality robust software that computes the BROJA PID measure based on the Cone Programming model. In this paper, we prove the important property of strong duality for the Cone Program and prove an equivalence between the Cone Program and the original Convex problem. Then, we describe in detail our software, explain how to use it, and perform some experiments comparing it to other estimators. Finally, we show that the software can be extended to compute some quantities of a trivaraite PID measure.

Antitumor effectiveness and mechanism of action of Ru(II)/amino acid/diphosphine complexes in the peritoneal carcinomatosis progression.

Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF6(1) and the [Ru(l-Trp)(bipy)(dppb)]PF6(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg-1) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.

Multiagent cooperation and competition with deep reinforcement learning.

Evolution of cooperation and competition can appear when multiple adaptive agents share a biological, social, or technological niche. In the present work we study how cooperation and competition emerge between autonomous agents that learn by reinforcement while using only their raw visual input as the state representation. In particular, we extend the Deep Q-Learning framework to multiagent environments to investigate the interaction between two learning agents in the well-known video game Pong. By manipulating the classical rewarding scheme of Pong we show how competitive and collaborative behaviors emerge. We also describe the progression from competitive to collaborative behavior when the incentive to cooperate is increased. Finally we show how learning by playing against another adaptive agent, instead of against a hard-wired algorithm, results in more robust strategies. The present work shows that Deep Q-Networks can become a useful tool for studying decentralized learning of multiagent systems coping with high-dimensional environments.

VREX: an open-source toolbox for creating 3D virtual reality experiments.

BACKGROUND: We present VREX, a free open-source Unity toolbox for virtual reality research in the fields of experimental psychology and neuroscience. RESULTS: Different study protocols about perception, attention, cognition and memory can be constructed using the toolbox. VREX provides a procedural generation of (interconnected) rooms that can be automatically furnished with a click of a button. VREX includes a menu system for creating and storing experiments with different stages. Researchers can combine different rooms and environments to perform end-to-end experiments including different testing situations and data collection. For fine-tuned control VREX also comes with an editor where all the objects in the virtual room can be manually placed and adjusted in the 3D world. CONCLUSIONS: VREX simplifies the generation and setup of complicated VR scenes and experiments for researchers. VREX can be downloaded and easily installed from vrex.mozello.com.