Search

Science is increasingly done in large teams, making it more likely that papers will be written by several authors from different institutes, disciplines, and cultural backgrounds. A small number of “Ten simple rules” papers have been written on collaboration and on writing but not on combining the two. Collaborative writing with multiple authors has additional challenges, including varied levels of engagement of coauthors, provision of fair credit through authorship or acknowledgements, acceptance of a diversity of work styles, and the need for clear communication. Miscommunication, a lack of leadership, and inappropriate tools or writing approaches can lead to frustration, delay of publication, or even the termination of a project. To provide insight into collaborative writing, we use our experience from the Global Lake Ecological Observatory Network (GLEON) to frame 10 simple rules for collaboratively writing a multi-authored paper. We consider a collaborative multi-authored paper to have three or more people from at least two different institutions. A multi-authored paper can be a result of a single discrete research project or the outcome of a larger research program that includes other papers based on common data or methods. The writing of a multi-authored paper is embedded within a broader context of planning and collaboration among team members. Our recommended rules include elements of both the planning and writing of a paper, and they can be iterative, although we have listed them in numerical order. It will help to revisit the rules frequently throughout the writing process. With the 10 rules outlined below, we aim to provide a foundation for writing multi-authored papers and conducting exciting and influential science.

“There is no problem that a library card can't solve” according to author Eleanor Brown [1]. This advice is sound, probably for both life and science, but even the best tool (like the library) is most effective when accompanied by instructions and a basic understanding of how and when to use it. For many budding scientists, the first day in a new lab setting often involves a stack of papers, an email full of links to pertinent articles, or some promise of a richer understanding so long as one reads enough of the scientific literature. However, the purpose and approach to reading a scientific article is unlike that of reading a news story, novel, or even a textbook and can initially seem unapproachable. Having good habits for reading scientific literature is key to setting oneself up for success, identifying new research questions, and filling in the gaps in one’s current understanding; developing these good habits is the first crucial step. Advice typically centers around two main tips: read actively and read often. However, active reading, or reading with an intent to understand, is both a learned skill and a level of effort. Although there is no one best way to do this, we present 10 simple rules, relevant to novices and seasoned scientists alike, to teach our strategy for active reading based on our experience as readers and as mentors of undergraduate and graduate researchers, medical students, fellows, and early career faculty. Rules 1–5 are big picture recommendations. Rules 6–8 relate to philosophy of reading. Rules 9–10 guide the “now what?” questions one should ask after reading and how to integrate what was learned into one’s own science.

A game of rock-paper-scissors is an interesting example of an interaction where none of the pure strategies strictly dominates all others, leading to a cyclic pattern. In this work, we consider an unstable version of rock-paper-scissors dynamics and allow individuals to make behavioural mistakes during the strategy execution. We show that such an assumption can break a cyclic relationship leading to a stable equilibrium emerging with only one strategy surviving. We consider two cases: completely random mistakes when individuals have no bias towards any strategy and a general form of mistakes. Then, we determine conditions for a strategy to dominate all other strategies. However, given that individuals who adopt a dominating strategy are still prone to behavioural mistakes in the observed behaviour, we may still observe extinct strategies. That is, behavioural mistakes in strategy execution stabilise evolutionary dynamics leading to an evolutionary stable and, potentially, mixed co-existence equilibrium., Author summary A game of rock-paper-scissors is more than just a children’s game. This type of interactions is often used to describe competition among animals or humans. A special feature of such an interaction is that none of the pure strategies dominates, resulting in a cyclic pattern. However, in wild communities such interactions are rarely observed by biologists. Our results suggest that this lack of cyclicity may stem from imperfectness of interacting individuals. In other words, we show analytically that heterogeneity in behavioural patterns may break a cyclic relationship and lead to a stable equilibrium in pure or mixed strategies.

In their Commentary paper, Villaverde and Massonis (On testing structural identifiability by a simple scaling method: relying on scaling symmetries can be misleading) have commented on our paper in which we proposed a simple scaling method to test structural identifiability. Our scaling invariance method (SIM) tests for scaling symmetries only, and Villaverde and Massonis correctly show the SIM may fail to detect identifiability problems when a model has other types of symmetries. We agree with the limitations raised by these authors but, also, we emphasize that the method is still valuable for its applicability to a wide variety of models, its simplicity, and even as a tool to introduce the problem of identifiability to investigators with little training in mathematics.

Overfitting is one of the critical problems in developing models by machine learning. With machine learning becoming an essential technology in computational biology, we must include training about overfitting in all courses that introduce this technology to students and practitioners. We here propose a hands-on training for overfitting that is suitable for introductory level courses and can be carried out on its own or embedded within any data science course. We use workflow-based design of machine learning pipelines, experimentation-based teaching, and hands-on approach that focuses on concepts rather than underlying mathematics. We here detail the data analysis workflows we use in training and motivate them from the viewpoint of teaching goals. Our proposed approach relies on Orange, an open-source data science toolbox that combines data visualization and machine learning, and that is tailored for education in machine learning and explorative data analysis., Author summary Every teacher strives for an a-ha moment, a sudden revelation by the student who gained a fundamental insight she will always remember. In the past years, authors of this paper have been tailoring their courses in machine learning to include material that could lead students to such discoveries. We aim to expose machine learning to practitioners–not only computer scientists but also molecular biologists and students of biomedicine, that is, the end-users of bioinformatics’ computational approaches. In this article, we lay out a course that aims to teach about overfitting, one of the key concepts in machine learning that needs to be understood, mastered, and avoided in data science applications. We propose a hands-on approach that uses an open-source workflow-based data science toolbox that combines data visualization and machine learning. In the proposed training about overfitting, we first deceive the students, then expose the problem, and finally challenge them to find the solution. In the paper, we present three lessons in overfitting and associated data analysis workflows and motivate the use of introduced computation methods by relating them to concepts conveyed by instructors.

This paper uses mathematical modeling to study the mechanisms of surround suppression in the primate visual cortex. We present a large-scale neural circuit model consisting of three interconnected components: LGN and two input layers (Layer 4Ca and Layer 6) of the primary visual cortex V1, covering several hundred hypercolumns. Anatomical structures are incorporated and physiological parameters from realistic modeling work are used. The remaining parameters are chosen to produce model outputs that emulate experimentally observed size-tuning curves. Our two main results are: (i) we discovered the character of the long-range connections in Layer 6 responsible for surround effects in the input layers; and (ii) we showed that a net-inhibitory feedback, i.e., feedback that excites I-cells more than E-cells, from Layer 6 to Layer 4 is conducive to producing surround properties consistent with experimental data. These results are obtained through parameter selection and model analysis. The effects of nonlinear recurrent excitation and inhibition are also discussed. A feature that distinguishes our model from previous modeling work on surround suppression is that we have tried to reproduce realistic lengthscales that are crucial for quantitative comparison with data. Due to its size and the large number of unknown parameters, the model is computationally challenging. We demonstrate a strategy that involves first locating baseline values for relevant parameters using a linear model, followed by the introduction of nonlinearities where needed. We find such a methodology effective, and propose it as a possibility in the modeling of complex biological systems., Author summary The visual cortex is a part of the cortex that processes visual signal. The visual signal from the retina is relayed through the lateral geniculate nucleus (LGN), and enters the primary visual cortex directly. The primary visual cortex consists of many layers. A phenomenon called surround suppression, which means a reduction of neuronal activities in response to stimuli of increasing size, is well-observed in all layers of the primate primary visual cortex. In this paper, we built a large scale mathematical model consisting of the LGN input and tens of thousands of neuron groups in Layer 4 and Layer 6 of the primary visual cortex to study the mechanism of surround suppression. This model is constrained by both anatomical structures and realistic physiological parameters. Remaining unknown parameters are reverse-engineered from experimental data. We showed how the character of the surround suppression depends on the long-range connections in the feedback layer, as well as the feedback current from Layer 6 to Layer 4.

Humans are able to track multiple objects at any given time in their daily activities—for example, we can drive a car while monitoring obstacles, pedestrians, and other vehicles. Several past studies have examined how humans track targets simultaneously and what underlying behavioral and neural mechanisms they use. At the same time, computer-vision researchers have proposed different algorithms to track multiple targets automatically. These algorithms are useful for video surveillance, team-sport analysis, video analysis, video summarization, and human–computer interaction. Although there are several efficient biologically inspired algorithms in artificial intelligence, the human multiple-target tracking (MTT) ability is rarely imitated in computer-vision algorithms. In this paper, we review MTT studies in neuroscience and biologically inspired MTT methods in computer vision and discuss the ways in which they can be seen as complementary., Author summary Multiple-target tracking (MTT) is a challenging task vital for both a human’s daily life and for many artificial intelligent systems, such as those used for urban traffic control. Neuroscientists are interested in discovering the underlying neural mechanisms that successfully exploit cognitive resources, e.g., spatial attention or memory, during MTT. Computer-vision specialists aim to develop powerful MTT algorithms based on advanced models or data-driven computational methods. In this paper, we review MTT studies from both communities and discuss how findings from cognitive studies can inspire developers to construct higher performing MTT algorithms. Moreover, some directions have been proposed through which MTT algorithms could raise new questions in the cognitive science domain, and answering them can shed light on neural processes underlying MTT.

Learning the reliability of different sources of rewards is critical for making optimal choices. However, despite the existence of detailed theory describing how the expected reward is learned in the basal ganglia, it is not known how reward uncertainty is estimated in these circuits. This paper presents a class of models that encode both the mean reward and the spread of the rewards, the former in the difference between the synaptic weights of D1 and D2 neurons, and the latter in their sum. In the models, the tendency to seek (or avoid) options with variable reward can be controlled by increasing (or decreasing) the tonic level of dopamine. The models are consistent with the physiology of and synaptic plasticity in the basal ganglia, they explain the effects of dopaminergic manipulations on choices involving risks, and they make multiple experimental predictions., Author Summary To maximize their chances for survival, animals need to base their decisions not only on the average consequences of chosen actions, but also on the variability of the rewards resulting from these actions. For example, when an animal’s food reserves are depleted, it should prefer to forage in an area where food is guaranteed over an area where the amount of food is higher on average but variable, thus avoiding the risk of starvation. To implement such policies, animals need to be able to learn about variability of rewards resulting from taking different actions. This paper proposes how such learning may be implemented in a circuit of subcortical nuclei called the basal ganglia. It also suggests how the information about reward uncertainty can be used during decision making, so that animals can make choices that not only maximize expected rewards but also minimize risks.

The free-energy principle has recently been proposed as a unified Bayesian account of perception, learning and action. Despite the inextricable link between emotion and cognition, emotion has not yet been formulated under this framework. A core concept that permeates many perspectives on emotion is valence, which broadly refers to the positive and negative character of emotion or some of its aspects. In the present paper, we propose a definition of emotional valence in terms of the negative rate of change of free-energy over time. If the second time-derivative of free-energy is taken into account, the dynamics of basic forms of emotion such as happiness, unhappiness, hope, fear, disappointment and relief can be explained. In this formulation, an important function of emotional valence turns out to regulate the learning rate of the causes of sensory inputs. When sensations increasingly violate the agent's expectations, valence is negative and increases the learning rate. Conversely, when sensations increasingly fulfil the agent's expectations, valence is positive and decreases the learning rate. This dynamic interaction between emotional valence and learning rate highlights the crucial role played by emotions in biological agents' adaptation to unexpected changes in their world., Author Summary Emotion plays a crucial role in the adaptation of humans and other animals to changes in their world. Nevertheless, emotion has been neglected in Bayesian models of learning in non-stationary environments. The free-energy principle has recently been proposed as a unified account of learning, perception and action in biological agents. In this paper, we propose a formal definition of emotional valence (i.e., the positive and negative character of emotion) in terms of the rate of change of free-energy or, under some simplifying assumptions, of prediction error over time. This formalization leads to a straightforward and simple meta-learning scheme that accounts for the complex and reciprocal interaction between cognition and emotion. We instantiate this scheme with an emotional agent who is able to dynamically assign emotional valence to every new state of the world that is visited and to experience basic forms of emotion. Crucially, our hypothetical agent uses emotional valence to dynamically adapt to unexpected changes in the world. The proposed scheme is very general in the sense that it is not tied to any particular generative model of sensory inputs.

As science becomes increasingly interdisciplinary, we are expected to acquire both breadth of knowledge and depth of expertise. In bioinformatics, this is especially true. Keeping up to date with major techniques across multiple specialisations can be daunting, but you need not face it alone. A journal club is an excellent way to take in the scientific literature, keep up with developments in your field, and hone your communication and analytical skills. In general, a journal club is a group of people who meet regularly to discuss one or more scientific papers. The structure of such a club can vary. In the more traditional format, an individual studies a paper and then presents it to the group, usually in the form of PowerPoint slides, with time for questions. In some institutions, the journal club is for students only, designed to fulfill the requirements of a course or postgraduate program; attendance is obligatory, the scope of the literature is narrow, and the format is prescribed. The preparation of slides and a lecture may be required. Other kinds of journal clubs are just lab meetings in disguise, with the usual lab head and group members in attendance and one member nominated to present the paper. A formal style often fits well within an established academic structure—but what if your discipline is emerging? Consider the field of bioinformatics. Expertise may be spread across departments and institutions, and there may not be an obvious place or critical mass in any one lab for a traditional journal club. Research students, “pet bioinformaticians,” [1] and those interested in bioinformatics from adjoining fields all need a place to gather. We are pleased to offer an alternative structure to address this situation—an informal journal club, designed to bring together a diversity of backgrounds and career stages to discuss bioinformatics while building a network of like-minded peers. Additional benefits of such a journal club may include friendship and breakfast (see Rule 2)! We thoroughly recommend it to anyone who asks (as well as those who don’t). While this advice is drawn from our experiences in the Parkville Bioinformatics Journal Club, it is applicable to developing informal journal clubs of all disciplines. The advice contained in these rules will also help those who want to spice up their existing formal format. So don’t be a “lonely bioinformatician”[1], create a journal club! Follow these Ten Simple Rules to find out how.

The spread of infectious diseases such as COVID-19 presents many challenges to healthcare systems and infrastructures across the world, exacerbating inequalities and leaving the world’s most vulnerable populations most affected. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to disease spread. In this paper we present an agent-based modeling approach to simulating the spread of disease in refugee and IDP settlements under various non-pharmaceutical intervention strategies. The model, based on the June open-source framework, is informed by data on geography, demographics, comorbidities, physical infrastructure and other parameters obtained from real-world observations and previous literature. The development and testing of this approach focuses on the Cox’s Bazar refugee settlement in Bangladesh, although our model is designed to be generalizable to other informal settings. Our findings suggest the encouraging self-isolation at home of mild to severe symptomatic patients, as opposed to the isolation of all positive cases in purpose-built isolation and treatment centers, does not increase the risk of secondary infection meaning the centers can be used to provide hospital support to the most intense cases of COVID-19. Secondly we find that mask wearing in all indoor communal areas can be effective at dampening viral spread, even with low mask efficacy and compliance rates. Finally, we model the effects of reopening learning centers in the settlement under various mitigation strategies. For example, a combination of mask wearing in the classroom, halving attendance regularity to enable physical distancing, and better ventilation can almost completely mitigate the increased risk of infection which keeping the learning centers open may cause. These modeling efforts are being incorporated into decision making processes to inform future planning, and further exercises should be carried out in similar geographies to help protect those most vulnerable., Author summary The spread of infectious diseases presents many challenges to healthcare systems and infrastructures across the world. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to the dangers of disease spread. This study seeks to understand how COVID-19 spreads in settlements, focusing on the Cox’s Bazar refugee settlement in Bangladesh. Our model simulates the movements and interactions of each individual in the settlement, incorporating information about family structures and demographic attributes, to understand how COVID-19 might spread under various intervention strategies. Our analysis suggests that mask wearing in indoor locations can have a significant effect on disease spread, even when wearing reusable cotton masks, which the people in the settlement can make themselves. We also look at different ways to treat individuals who only have milder symptoms and don’t yet require hospitalisation, as well as various scenarios which might allow for the safe reopening of schools in the settlement. With almost 80 million forcibly displaced people in the world, we hope that this work will inspire more modeling groups to focus on these vulnerable populations, which have been traditionally under-served by such efforts, to ensure no one is left behind.

System identification techniques -- projection pursuit regression models (PPRs) and convolutional neural networks (CNNs) -- provide state-of-the-art performance in predicting visual cortical neurons' responses to arbitrary input stimuli. However, the constituent kernels recovered by these methods are often noisy and lack coherent structure, making it difficult to understand the underlying component features of a neuron's receptive field. In this paper, we show that using a dictionary of diverse kernels with complex shapes learned from natural scenes based on efficient coding theory, as the front-end for PPRs and CNNs can improve their performance in neuronal response prediction as well as algorithmic data efficiency and convergence speed. Extensive experimental results also indicate that these sparse-code kernels provide important information on the component features of a neuron's receptive field. In addition, we find that models with the complex-shaped sparse code front-end are significantly better than models with a standard orientation-selective Gabor filter front-end for modeling V1 neurons that have been found to exhibit complex pattern selectivity. We show that the relative performance difference due to these two front-ends can be used to produce a sensitive metric for detecting complex selectivity in V1 neurons., 22 pages

Animals rely on sensory feedback to generate accurate, reliable movements. In many flying insects, strain-sensitive neurons on the wings provide rapid feedback that is critical for stable flight control. While the impacts of wing structure on aerodynamic performance have been widely studied, the impacts of wing structure on sensing are largely unexplored. In this paper, we show how the structural properties of the wing and encoding by mechanosensory neurons interact to jointly determine optimal sensing strategies and performance. Specifically, we examine how neural sensors can be placed effectively on a flapping wing to detect body rotation about different axes, using a computational wing model with varying flexural stiffness. A small set of mechanosensors, conveying strain information at key locations with a single action potential per wingbeat, enable accurate detection of body rotation. Optimal sensor locations are concentrated at either the wing base or the wing tip, and they transition sharply as a function of both wing stiffness and neural threshold. Moreover, the sensing strategy and performance is robust to both external disturbances and sensor loss. Typically, only five sensors are needed to achieve near-peak accuracy, with a single sensor often providing accuracy well above chance. Our results show that small-amplitude, dynamic signals can be extracted efficiently with spatially and temporally sparse sensors in the context of flight. The demonstrated interaction of wing structure and neural encoding properties points to the importance of understanding each in the context of their joint evolution., Author summary In addition to generating forces for flight, insect wings also serve an important role as sensory structures, providing rapid feedback about wing bending that is used to stabilize flight. While much is known about how wing structure affects aerodynamic performance, the effects of wing structure on sensing remain unexplored. Using a computational model of a flapping wing, we examine how sensing strategies depend on wing stiffness and sensor properties. We show that body rotations can be accurately detected with a small number of sensors on the wing across a wide range of conditions. Optimal sensor locations are clustered at either the wing base or wing tip, depending on a combination of wing stiffness and sensor properties. Moreover, sensing performance is robust to multiple kinds of perturbations. Our work provides a basis for understanding how wing structure impacts incoming sensory information during flight.

© 2021 Moore et al., Bioinformatics training is required at every stage of a scientist’s research career. Continual bioinformatics training allows exposure to an ever-changing and growing repertoire of techniques and databases, and so biologists, computational scientists, and healthcare practitioners are all seeking learning opportunities in the use of computational resources and tools designed for data storage, retrieval, and analysis. There are abundant opportunities for accessing bioinformatics training for scientists in high-income countries (HICs), with well-equipped facilities and participants and trainers requiring minimal travel and financial costs alongside a range of general advice for developing short bioinformatics training courses [1–3]. However, regionally targeted bioinformatics training in low- and middle-income countries (LMICs) often requires more extensive local and external support, organization, and travel. Due to the limited expertise in bioinformatics in LMICs in general, most bioinformatics training requires a fair amount of collaboration with experts beyond the local community, country, or region. A common model of training, used as the basis of this article, includes a local host collaborating with local, regional, and international experts gathering to train local or regional participants. Recently, there has been a growth of capacity strengthening initiatives in LMICs, such as the Pan African Bioinformatics Network for Human Heredity and Health in Africa (H3ABioNet) Initiative [4–6], the Capacity Building for Bioinformatics in Latin America (CABANA) Project [7], the Asia Pacific BioInformatics Network (APBioNet) [8], and the Wellcome Connecting Science Courses and Conferences program [9]. One of the important strands of these initiatives is a drive to organize and deliver valuable bioinformatics training, but organizing and delivering short bioinformatics training workshops in an LMIC present a unique set of challenges. This paper attempts to build upon the sage advice for organizing bioinformatics workshops with specific guidance for organizing and delivering them in LMICs. It describes the processes to follow in organizing courses taking into consideration the low-resource setting. We should also note that LMICs are not a monolithic group and that setting, context, temporality, and specific location matters. LMICs are a complex regional grouping [10] and should be treated as such; however, we will present some common lessons that we hope will help organizers and trainers of bioinformatics training events in LMICs to navigate the often different, challenging, and rewarding experience., The authors who contributed to this manuscript are funded as follows: BM receives salary support from Wellcome Trust grants [WT108749/Z/15/Z, WT108749/Z/15/A], PC, VR, NM, AG’s salaries are funded in whole, or in part, by the NIH Common Fund H3ABioNet grant [U24HG006941], MC, SLFV, AR, PG, PCL’s salaries were partly funded by the UKRI-BBSRC ‘Capacity building for bioinformatics in Latin America’ (CABANA) grant, on behalf of the Global Challenges Research Fund [BB/P027849/1], JDLR is funded by ISCiii AES [ref. PI18/00591] at the CSIC/USAL (Spain) and by CYTED, RIABIO (Red Iberoamericana 521RT0118), AM’s salary is funded by [WT206194/Z/17/Z], GO is funded by the CABANA grant and SM is funded by the EMBL-EBI.

Because local field potentials (LFPs) arise from multiple sources in different spatial locations, they do not easily reveal coordinated activity across neural populations on a trial-to-trial basis. As we show here, however, once disparate source signals are decoupled, their trial-to-trial fluctuations become more accessible, and cross-population correlations become more apparent. To decouple sources we introduce a general framework for estimation of current source densities (CSDs). In this framework, the set of LFPs result from noise being added to the transform of the CSD by a biophysical forward model, while the CSD is considered to be the sum of a zero-mean, stationary, spatiotemporal Gaussian process, having fast and slow components, and a mean function, which is the sum of multiple time-varying functions distributed across space, each varying across trials. We derived biophysical forward models relevant to the data we analyzed. In simulation studies this approach improved identification of source signals compared to existing CSD estimation methods. Using data recorded from primate auditory cortex, we analyzed trial-to-trial fluctuations in both steady-state and task-evoked signals. We found cortical layer-specific phase coupling between two probes and showed that the same analysis applied directly to LFPs did not recover these patterns. We also found task-evoked CSDs to be correlated across probes, at specific cortical depths. Using data from Neuropixels probes in mouse visual areas, we again found evidence for depth-specific phase coupling of primary visual cortex and lateromedial area based on the CSDs., Author summary To better understand information processing in the brain, it is important to identify situations in which neural activity is coordinated across populations of neurons, including those in distinct layers of the cortex. Bulk population activity results in voltage changes across extracellular electrodes, but in raw form such voltage recordings can be hard to analyze and interpret. In this paper, we develop a novel framework for locating the sources of currents that produce the measured voltages, and decomposing those currents into interpretable components. We use this flexible framework to develop statistical methods of analysis, and we show that our methodology can be more effective than existing techniques for current source localization. We apply the method to extracellular recordings in two contexts: primate auditory cortex in response to tone stimuli, and mouse visual cortex in response to visual stimuli. In both cases, we get results that are useful for understanding cross-population activity while being difficult or impossible to obtain using the raw voltage signals. We thereby demonstrate the broad utility of our approach for identifying coordinated neural activity based on extracellular voltage recordings.

Our cognition relies on the ability of the brain to segment hierarchically structured events on multiple scales. Recent evidence suggests that the brain performs this event segmentation based on the structure of state-transition graphs behind sequential experiences. However, the underlying circuit mechanisms are poorly understood. In this paper we propose an extended attractor network model for graph-based hierarchical computation which we call the Laplacian associative memory. This model generates multiscale representations for communities (clusters) of associative links between memory items, and the scale is regulated by the heterogenous modulation of inhibitory circuits. We analytically and numerically show that these representations correspond to graph Laplacian eigenvectors, a popular method for graph segmentation and dimensionality reduction. Finally, we demonstrate that our model exhibits chunked sequential activity patterns resembling hippocampal theta sequences. Our model connects graph theory and attractor dynamics to provide a biologically plausible mechanism for abstraction in the brain., Author summary Our experiences are often hierarchically organized, so is our knowledge. Identifying meaningful segments in hierarchically structured information is crucial for many cognitive functions including visual, auditory, motor, memory, language processing, and reasoning. Herein, we show that the attractor dynamics of recurrent neural circuits offer a biologically plausible way for hierarchical segmentation. We found that an extended model of associative memory autonomously performs segmentation by finding groups of tightly linked memories. We proved that the neural dynamics of our model mathematically coincide with optimal graph segmentation in graph theory and are consistent with the experimentally observed nature of human behaviors and neural activities. Our model established a previously unexpected relationship between attractor neural networks and the graph-theoretic processing of knowledge structures. Our model also provides experimentally testable predictions, particularly regarding the role of inhibitory circuits in controlling representational granularity.

There are two distinct classes of cells in the primary visual cortex (V1): simple cells and complex cells. One defining feature of complex cells is their spatial phase invariance; they respond strongly to oriented grating stimuli with a preferred orientation but with a wide range of spatial phases. A classical model of complete spatial phase invariance in complex cells is the energy model, in which the responses are the sum of the squared outputs of two linear spatially phase-shifted filters. However, recent experimental studies have shown that complex cells have a diverse range of spatial phase invariance and only a subset can be characterized by the energy model. While several models have been proposed to explain how complex cells could learn to be selective to orientation but invariant to spatial phase, most existing models overlook many biologically important details. We propose a biologically plausible model for complex cells that learns to pool inputs from simple cells based on the presentation of natural scene stimuli. The model is a three-layer network with rate-based neurons that describes the activities of LGN cells (layer 1), V1 simple cells (layer 2), and V1 complex cells (layer 3). The first two layers implement a recently proposed simple cell model that is biologically plausible and accounts for many experimental phenomena. The neural dynamics of the complex cells is modeled as the integration of simple cells inputs along with response normalization. Connections between LGN and simple cells are learned using Hebbian and anti-Hebbian plasticity. Connections between simple and complex cells are learned using a modified version of the Bienenstock, Cooper, and Munro (BCM) rule. Our results demonstrate that the learning rule can describe a diversity of complex cells, similar to those observed experimentally., Author summary Many cortical functions originate from the learning ability of the brain. How the properties of cortical cells are learned is vital for understanding how the brain works. There are many models that explain how V1 simple cells can be learned. However, how V1 complex cells are learned still remains unclear. In this paper, we propose a model of learning in complex cells based on the Bienenstock, Cooper, and Munro (BCM) rule. We demonstrate that properties of receptive fields of complex cells can be learned using this biologically plausible learning rule. Quantitative comparisons between the model and experimental data are performed. Results show that model complex cells can account for the diversity of complex cells found in experimental studies. In summary, this study provides a plausible explanation for how complex cells can be learned using biologically plausible plasticity mechanisms. Our findings help us to better understand biological vision processing and provide us with insights into the general signal processing principles that the visual cortex employs to process visual information.

Slow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates with memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events’ co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0°, 45°, and 90° of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0° stimulation produces better results in the power and number of SO and SP than the rhythmic or random stimulation. On the other hand, stimulating at 45° or 90° change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0° phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work., Author summary During the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus –shape, amplitude, duration, periodicity– would be optimal for increasing the events’ frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.

We propose a developmental model inspired by the cortico-basal system (CX-BG) for vocal learning in babies and for solving the correspondence mismatch problem they face when they hear unfamiliar voices, with different tones and pitches. This model is based on the neural architecture INFERNO standing for Iterative Free-Energy Optimization of Recurrent Neural Networks. Free-energy minimization is used for rapidly exploring, selecting and learning the optimal choices of actions to perform (eg sound production) in order to reproduce and control as accurately as possible the spike trains representing desired perceptions (eg sound categories). We detail in this paper the CX-BG system responsible for linking causally the sound and motor primitives at the order of a few milliseconds. Two experiments performed with a small and a large audio database show the capabilities of exploration, generalization and robustness to noise of our neural architecture in retrieving audio primitives during vocal learning and during acoustic matching with unheared voices (different genders and tones)., Author summary We designed a developmental architecture inspired by the cortico-basal system for early vocal learning. Our neural system explores, evaluates and strengthens the motor primitives that match the best the sound repertoire created also dynamically. After a babbling process in which the network tests and aligns pronounced sound and motor vocal tracks, it is used for listening to novel voices, solving the correspondence problem.

When we face ambiguous images, the brain cannot commit to a single percept; instead, it switches between mutually exclusive interpretations every few seconds, a phenomenon known as bistable perception. While neuromechanistic models, e.g., adapting neural populations with lateral inhibition, may account for the dynamics of bistability, a larger question remains unresolved: how this phenomenon informs us on generic perceptual processes in less artificial contexts. Here, we propose that bistable perception is due to our prior beliefs being reverberated in the cortical hierarchy and corrupting the sensory evidence, a phenomenon known as “circular inference”. Such circularity could occur in a hierarchical brain where sensory responses trigger activity in higher-level areas but are also modulated by feedback projections from these same areas. We show that in the face of ambiguous sensory stimuli, circular inference can change the dynamics of the perceptual system and turn what should be an integrator of inputs into a bistable attractor switching between two highly trusted interpretations. The model captures various aspects of bistability, including Levelt’s laws and the stabilizing effects of intermittent presentation of the stimulus. Since it is related to the generic perceptual inference and belief updating mechanisms, this approach can be used to predict the tendency of individuals to form aberrant beliefs from their bistable perception behavior. Overall, we suggest that feedforward/feedback information loops in hierarchical neural networks, a phenomenon that could lead to psychotic symptoms when overly strong, could also underlie perception in nonclinical populations., Author summary In cases of high ambiguity, our perceptual system cannot commit to a single percept and switches between different interpretations, giving rise to bistable perception. In this paper we outline a computational model of bistability based on the notion of circular inference, i.e. a form of suboptimal hierarchical inference in which priors and / or sensory inputs are reverberated and over-counted. We suggest that descending loops (i.e. reverberated priors) transform our perceptual system from a simple accumulator of sensory inputs into a bistable attractor, that switches between two highly-trusted interpretations. Using analytical methods we derive the necessary conditions for bistable perception to occur. We show that our dynamical circular inference model is able to capture many features of bistability, such as Levelt’s laws and the stabilizing effects of intermittent presentation of the stimulus. Finally we make novel predictions about the behavior of psychotic patients.

Contributing to broader impacts is an important aspect of scientific research. Engaging practicing K-12 teachers as part of a research project can be an effective approach for addressing broader impacts requirements of grants, while also advancing researcher and teacher professional growth. Our focus is on leveraging teachers' professional expertise to develop science education materials grounded in emerging scientific research. In this paper, we describe ten simple rules for planning, implementing, and evaluating teacher engagement to support the broader impact goals of your research project. These collaborations can lead to the development of instructional materials or activities for students in the classroom or provide science research opportunities for teachers. We share our successes and lessons learned while collaborating with high school biology teachers to create technology-based, instructional materials developed from basic biological research. The rules we describe are applicable across teacher partnerships at any grade level in that they emphasize eliciting and respecting teachers' professionalism and expertise.

Learning transfer (i.e. accelerated learning over a series of structurally related learning tasks) differentiates species and age-groups, but the evolutionary and developmental implications of such differences are unclear. To this end, the relational schema induction paradigm employing tasks that share algebraic (group-like) structures was introduced to contrast stimulus-independent (relational) versus stimulus-dependent (associative) learning processes. However, a theory explaining this kind of relational learning transfer has not been forthcoming beyond a general appeal to some form of structure-mapping, as typically assumed in models of analogy. In this paper, we provide a theory of relational schema induction as a “reconstruction” process: the algebraic structure underlying transfer is reconstructed by comparing stimulus relations, learned within each task, for structural consistency across tasks—formally, the theory derives from a category theory version of Tannakian reconstruction. The theory also applies to non-human studies of relational concepts, thereby placing human and non-human transfer on common ground for sharper comparison and contrast. As the theory and paradigm do not depend on linguistic ability, we also have a way for pinpointing where aspects of human learning diverge from other species without begging the question of language., Author summary Learning transfer—an improvement in the rate of learning over a series of learning tasks—differs between species and age-groups, but the implications of such differences are unclear. Relational schema induction is a form of learning transfer that highlights relational aspects of learning. However, a theory explaining this kind of induction and transfer has not been forthcoming beyond a general appeal to some form of analogical mapping, as typically assumed in models of analogy. I present a theory of relational schema induction as a “reconstruction” process: the common structure affording transfer is reconstructed by comparing stimulus relations learned within each task for structural consistency across tasks. The theory also applies to non-human studies of relational concepts, thereby placing human and non-human studies on common ground for a clearer comparison and contrast.

Estimating the latent dynamics underlying biological processes is a central problem in computational biology. State-space models with Gaussian statistics are widely used for estimation of such latent dynamics and have been successfully utilized in the analysis of biological data. Gaussian statistics, however, fail to capture several key features of the dynamics of biological processes (e.g., brain dynamics) such as abrupt state changes and exogenous processes that affect the states in a structured fashion. Although Gaussian mixture process noise models have been considered as an alternative to capture such effects, data-driven inference of their parameters is not well-established in the literature. The objective of this paper is to develop efficient algorithms for inferring the parameters of a general class of Gaussian mixture process noise models from noisy and limited observations, and to utilize them in extracting the neural dynamics that underlie auditory processing from magnetoencephalography (MEG) data in a cocktail party setting. We develop an algorithm based on Expectation-Maximization to estimate the process noise parameters from state-space observations. We apply our algorithm to simulated and experimentally-recorded MEG data from auditory experiments in the cocktail party paradigm to estimate the underlying dynamic Temporal Response Functions (TRFs). Our simulation results show that the richer representation of the process noise as a Gaussian mixture significantly improves state estimation and capturing the heterogeneity of the TRF dynamics. Application to MEG data reveals improvements over existing TRF estimation techniques, and provides a reliable alternative to current approaches for probing neural dynamics in a cocktail party scenario, as well as attention decoding in emerging applications such as smart hearing aids. Our proposed methodology provides a framework for efficient inference of Gaussian mixture process noise models, with application to a wide range of biological data with underlying heterogeneous and latent dynamics., Author summary While Gaussian statistics are widely-used in analyzing biological data, they are not able to fully capture the observed heterogeneity and abrupt changes in the dynamics that govern the underlying biological processes. A notable example of such a process is the ability of the human brain to focus attention on one speaker among many in a cocktail party and switch attention to any other at will. We propose a signal processing methodology to extract the dynamics of such switching processes from noisy biological data in a robust and computationally efficient manner, and apply them to experimentally-recoded magnetoencephalography data from the human brain under cocktail party settings. Our results provide new insight on the heterogeneous neural dynamics that govern auditory attention switching. While our proposed methodology can be readily used as a reliable alternative to existing approaches in studying auditory processing in the human brain, it is suitable to be applied to a wide range of biological data with underlying heterogeneous dynamics.

Teaching well is a craft like any other, and success often comes from an accumulation of small improvements rather than from any single large change. This paper describes 10 practices you can use when teaching programming (and other subjects). All are easy to adopt and have proven their value in institutional classrooms, intensive workshops, and other settings.

The spatial distribution of visual items allows us to infer the presence of latent causes in the world. For instance, a spatial cluster of ants allows us to infer the presence of a common food source. However, optimal inference requires the integration of a computationally intractable number of world states in real world situations. For example, optimal inference about whether a common cause exists based on N spatially distributed visual items requires marginalizing over both the location of the latent cause and 2N possible affiliation patterns (where each item may be affiliated or non-affiliated with the latent cause). How might the brain approximate this inference? We show that subject behaviour deviates qualitatively from Bayes-optimal, in particular showing an unexpected positive effect of N (the number of visual items) on the false-alarm rate. We propose several “point-estimating” observer models that fit subject behaviour better than the Bayesian model. They each avoid a costly computational marginalization over at least one of the variables of the generative model by “committing” to a point estimate of at least one of the two generative model variables. These findings suggest that the brain may implement partially committal variants of Bayesian models when detecting latent causes based on complex real world data., Author summary Perceptual systems are designed to make sense of fragmented sensory data by inferring common, latent causes. Seeing a cluster of insects might allow us to infer the presence of a common food source, whereas the same number of insects scattered over a larger area of land might not evoke the same suspicions. The ability to reliably make this inference based on statistical information about the environment is surprisingly non-trivial: making the best possible inference requires making full use of the probabilistic information provided by the sensory data, which would require considering a combinatorially explosive number of hypothetical world states. In this paper, we test human subjects on their ability to perform a causal detection task: subjects are asked to judge whether an underlying cause of clustering is present or absent, based on the spatial distribution of those items. We show that subjects do not reason optimally on this task, and that particular computational short cuts (“committing” to certain world states over others, rather than representing them all) might underlie perceptual decision-making in these causal detection schemes.

Hosting an artist in a scientific lab is likely a new experience for many scientists in the natural and engineering sciences, and perhaps also for many artists, yet it can be a very beneficial experience for both parties [1]. “Art and science are in a tension that is most fruitful when these disciplines observe and penetrate each other and experience how much of the other they themselves still contain” [2]. During our science and art collaborations in the last years, we have learned what connects and what separates our disciplines, how different yet common our worlds of working and thinking are, and how stimulating such collaborations can be. Although scientists and artists belong to two different cultural worlds, many share research as a congruent method to explore and understand the world around us. Often, scientific and artistic work spaces are indistinguishable as they are full of equipment, materials, tools, and computers to run experiments and analyze data [3,4]. Science and art are fundamentally connected through their focus on creativity [5]. Also, both scientists and artists deliberately venture into the public realm in the spirit of Hannah Arendt: “Humanity is never won in loneliness and never by handing one’s work over to the public. Only if you take your life and person[ality] into the venture of the public realm, will you reach [humanity]” [6]. At the most fundamental level, science and art both try to understand the world around us and to guide society to recognize and solve problems. Artistic and scientific research may also have much more in common than one expects at first sight: They both involve years of schools and personal development, they both involve trial and error, and the sharing of results with different communities. However, transdisciplinary cooperation requires openness, a willingness to take risks, the ability for self-reflection, respect, and esteem for the other culture as well as a lot of appreciative listening from both parties [7,8]. Our paper thus intends to serve as a practical guide for both, artists-in-residence and the hosting scientific lab to easier cross borders, to better collaborate, to better learn from each other, and to sustainably bridge the different cultures of science and the arts. Our discussion starts at the point where a decision for such an interaction has already taken place. Still wondering if this is for you? There is much to gain for both sides. For the scientists, for example, this interaction can be a source of new ideas and questions, offering new points of view. Some of us also felt that this interaction offered training in explaining research in clear, simple language, and provided opportunities for interfacing with the science-curious public in a curated context. For the artists, this can be about learning new tools, methods, and approaches and about the specific topics on which a lab works. Some of the following 10 “rules” apply more to the artist, some more to the hosting science lab, and some to both (Fig 1). Open in a separate window Fig 1 Summary of the 10 rules, arrayed from intellectual/philosophical to practical/logistical and divided into rules more applicable to the hosting science lab and rules relevant for both the hosting lab and the artist. Rule 1: Be open The basic mindset and attitude required for both scientists and artists is openness. Openness to new input, willingness to share ideas, and a sharing attitude. It is not at all required to have an artistic “inclination” on the part of the hosting scientist, but nothing can replace an open attitude. Be open to accept that research can be both: scientific research and artistic research (for a definition of artistic research, see [9]).

The olfactory system faces the difficult task of identifying an enormous variety of odors independent of their intensity. Primacy coding, where the odor identity is encoded by the receptor types that respond earliest, might provide a compact and informative representation that can be interpreted efficiently by the brain. In this paper, we analyze the information transmitted by a simple model of primacy coding using numerical simulations and statistical descriptions. We show that the encoded information depends strongly on the number of receptor types included in the primacy representation, but only weakly on the size of the receptor repertoire. The representation is independent of the odor intensity and the transmitted information is useful to perform typical olfactory tasks with close to experimentally measured performance. Interestingly, we find situations in which a smaller receptor repertoire is advantageous for discriminating odors. The model also suggests that overly sensitive receptor types could dominate the entire response and make the whole array useless, which allows us to predict how receptor arrays need to adapt to stay useful during environmental changes. Taken together, we show that primacy coding is more useful than simple binary and normalized coding, essentially because the sparsity of the odor representations is independent of the odor statistics, in contrast to the alternatives. Primacy coding thus provides an efficient odor representation that is independent of the odor intensity and might thus help to identify odors in the olfactory cortex., Author summary Humans can identify odors independent of their intensity. Experimental data suggest that this is accomplished by representing the odor identity by the earliest responding receptor types. Using theoretical modeling, we here show that such a primacy code outperforms alternative encodings and allows discriminating odors with close to experimentally measured performance. This performance depends strongly on the number of receptors considered in the primacy code, but the receptor repertoire size is less important. The model also suggests a strong evolutionary pressure on the receptor sensitivities, which could explain observed receptor copy number adaptations. By predicting psycho-physical experiments, the model will thus contribute to our understanding of the olfactory system.

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study., Author summary Dendritic cells harvest and display antigen to other immune cells, and motility is essential to their function. Dendritic cells use filopodia to pull themselves forward, and orient their filopodia based on signals received from chemokines. We developed a model of dendritic cell motion based on a force balance, in which pulling from filopodia (calculated from a well-established model of filopodial adhesion-clutch dynamics) is counterbalanced by adhesive friction, and where the angular orientation of filopodia is based on the strength of chemotactic signal. The model can explain directional motion in chemotactic gradients, as well as the effect of superposition of coincident gradients of chemokine on chemotaxis. The model also identifies conditions in which dendritic cells can be focused at a single location when confronted with countergradients of chemokine. The model makes specific prediction regarding dendritic cell motion and defines conditions for the design of extracorporeal devices for focusing the position of dendritic cells.

In this paper, we present a novel Bayesian adaptive dual controller (ADC) for autonomously programming deep brain stimulation devices. We evaluated the Bayesian ADC’s performance in the context of reducing beta power in a computational model of Parkinson’s disease, in which it was tasked with finding the set of stimulation parameters which optimally reduced beta power as fast as possible. Here, the Bayesian ADC has dual goals: (a) to minimize beta power by exploiting the best parameters found so far, and (b) to explore the space to find better parameters, thus allowing for better control in the future. The Bayesian ADC is composed of two parts: an inner parameterized feedback stimulator and an outer parameter adjustment loop. The inner loop operates on a short time scale, delivering stimulus based upon the phase and power of the beta oscillation. The outer loop operates on a long time scale, observing the effects of the stimulation parameters and using Bayesian optimization to intelligently select new parameters to minimize the beta power. We show that the Bayesian ADC can efficiently optimize stimulation parameters, and is superior to other optimization algorithms. The Bayesian ADC provides a robust and general framework for tuning stimulation parameters, can be adapted to use any feedback signal, and is applicable across diseases and stimulator designs., Author summary Deep brain stimulation (DBS) is an effective therapy for treating motor symptoms of Parkinson’s disease. However, the clinical success of DBS relies on selecting stimulation parameters that both relieve symptoms while avoiding side effects. Currently, DBS devices are programmed using a laborious trial-and-error process, requiring multiple clinic visits over the course of months. As DBS leads and algorithms become more complex, it will become impossible to select optimal DBS parameters manually. There is a clear need for an intelligent, automated approach to parameter tuning. We present a novel Bayesian adaptive dual controller (ADC), which can autonomously tune stimulation parameters. It uses a feedback signal measured from the patient to quantify the efficacy of a set of stimulation parameters, and uses this information to intelligently find the parameters which work best for each individual patient. The Bayesian ADC has the potential to improve DBS efficacy and reduce clinic visits by efficiently finding the best stimulation parameters.

The Hybrid Automata Library (HAL) is a Java Library developed for use in mathematical oncology modeling. It is made of simple, efficient, generic components that can be used to model complex spatial systems. HAL’s components can broadly be classified into: on- and off-lattice agent containers, finite difference diffusion fields, a GUI building system, and additional tools and utilities for computation and data collection. These components are designed to operate independently and are standardized to make them easy to interface with one another. As a demonstration of how modeling can be simplified using our approach, we have included a complete example of a hybrid model (a spatial model with interacting agent-based and PDE components). HAL is a useful asset for researchers who wish to build performant 1D, 2D and 3D hybrid models in Java, while not starting entirely from scratch. It is available on GitHub at https://github.com/MathOnco/HAL under the MIT License. HAL requires the Java JDK version 1.8 or later to compile and run the source code., Author summary In this paper we introduce the Hybrid Automata Library (HAL) with the purpose of simplifying the implementation and sharing of hybrid models for use in mathematical oncology. Hybrid modeling is used in oncology to create spatial models of tissue, typically by modeling cells using agent-based techniques, and by modeling diffusible chemicals using partial differential equations (PDEs). HAL’s key components are designed to run agent-based models, PDEs, and visualization. The components are standardized and are completely decoupled, so models can be built with any combination of them. We first explore the philosophy behind HAL, then summarize the components. Lastly we demonstrate how the components work together with an example of a hybrid model, and a walk-through of the code used to construct it. HAL is open-source and will produce identical results on any machine that supports Java 8 and above, making it highly portable. We recommend HAL to modelers interested in spatial dynamics, even those outside of mathematical oncology, as the components are general enough to facilitate a variety of model types. A community page that provides a download link and online documentation can be found at https://halloworld.org.

Visual neurons respond to static images with specific dynamics: neuronal responses sum sub-additively over time, reduce in amplitude with repeated or sustained stimuli (neuronal adaptation), and are slower at low stimulus contrast. Here, we propose a simple model that predicts these seemingly disparate response patterns observed in a diverse set of measurements–intracranial electrodes in patients, fMRI, and macaque single unit spiking. The model takes a time-varying contrast time course of a stimulus as input, and produces predicted neuronal dynamics as output. Model computation consists of linear filtering, expansive exponentiation, and a divisive gain control. The gain control signal relates to but is slower than the linear signal, and this delay is critical in giving rise to predictions matched to the observed dynamics. Our model is simpler than previously proposed related models, and fitting the model to intracranial EEG data uncovers two regularities across human visual field maps: estimated linear filters (temporal receptive fields) systematically differ across and within visual field maps, and later areas exhibit more rapid and substantial gain control. The model is further generalizable to account for dynamics of contrast-dependent spike rates in macaque V1, and amplitudes of fMRI BOLD in human V1., Author summary This paper contributes to modeling and understanding the neuronal dynamics of visual cortex in four ways. First, we proposed a model that describes stimulus-driven neuronal dynamics in a simple and intuitive way. Second, we applied the model to intracranial EEG data and found regularities of response dynamics across and within human visual field maps. Third, the model was generalizable across different ways of measuring brain activity, allowing us to potentially link the sources underlying diverse measurements. Fourth, we comprehensively summarized existing models of neuronal dynamics, and identified effective components that give rise to accurate prediction.

Cells use surface receptors to estimate concentrations of external ligands. Limits on the accuracy of such estimations have been well studied for pairs of ligand and receptor species. However, the environment typically contains many ligands, which can bind to the same receptors with different affinities, resulting in cross-talk. In traditional rate models, such cross-talk prevents accurate inference of concentrations of individual ligands. In contrast, here we show that knowing the precise timing sequence of stochastic binding and unbinding events allows one receptor to provide information about multiple ligands simultaneously and with a high accuracy. We show that such high-accuracy estimation of multiple concentrations can be realized with simple structural modifications of the familiar kinetic proofreading biochemical network diagram. We give two specific examples of such modifications. We argue that structural and functional features of real cellular biochemical sensory networks in immune cells, such as feedforward and feedback loops or ligand antagonism, sometimes can be understood as solutions to the accurate multi-ligand estimation problem., Author summary Cells live in chemically complex environments with many different chemical ligands around them. Can cells estimate concentrations of more ligands than they have receptor types? In this paper, we show that, surprisingly, the answer is “yes”, and the estimation can be implemented with simple biochemical components already present in many cells. Therefore, cells may “know” a lot more about their environment and thus may be able to implement more complex and accurate response strategies than was previously thought.

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets., Author summary Autism spectrum disorder (ASD) encompasses a family of neurological disorders characterized by limited social interaction and restricted repetitive behaviors. The number of children diagnosed with ASD has grown exponentially over the last four decades and is now estimated to affect ∼1.5% of children. Although ASD is currently diagnosed and treated based solely on psychometric tools, a biochemical view applicable to at least a subset of ASD cases is emerging. Abnormalities in folate-dependent one carbon metabolism and transsulfuration pathways can summarize a large number of observations of genetic and environmental effects that increase ASD predisposition. However, these complex, highly interconnected pathways require more advanced statistical models than the typical univariate models presented in the literature. Therefore, we developed multivariate statistical models that classify participants based on their neurological status and predict adaptive behavior in ASD. We emphasize that these models are cross-validated, helping to ensure that the results will generalize to new samples. The models developed herein have much stronger predictability than any existing approaches from the scientific literature.