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Recent advances in cognitive neuroscience have focused on using resting-state functional connectivity (RSFC) data from fMRI scans to more accurately predict human traits and behaviors. Traditional approaches generally analyze RSFC by correlating averaged time-series data across regions of interest (ROIs) or networks, which may overlook important spatial signal patterns. To address this limitation, we introduced a novel linear regression technique that estimates RSFC by predicting spatial brain activity patterns in a target ROI from those in a seed ROI. We applied both traditional and our novel RSFC estimation methods to a large-scale dataset from the Human Connectome Project and the Brain Genomics Superstruct Project, analyzing resting-state fMRI data to predict sex, age, personality traits, and psychological task performance. To enhance prediction accuracy, we developed an ensemble learner that combines these qualitatively different methods using a weighted average approach. Our findings revealed that hierarchical clustering of RSFC patterns using our novel method displays distinct whole-brain grouping patterns compared to the traditional approach. Importantly, the ensemble model, integrating these diverse weak learners, outperformed the traditional RSFC method in predicting human traits and behaviors. Notably, the predictions from the traditional and novel methods showed relatively low similarity, indicating that our novel approach captures unique and previously undetected information about human traits and behaviors through fine-grained local spatial patterns of neural activation. These results highlight the potential of combining traditional and innovative RSFC analysis techniques to enrich our understanding of the neural basis of human traits and behaviors., Competing Interests: Declaration of competing interest No, I declare the authors have no competing interests as defined by Neuroimage, or other interests that might be perceived to influence the interpretation of the article., (Copyright © 2024. Published by Elsevier Inc.)

Sleep is regulated by homeostatic processes, yet the biological basis of sleep pressure that accumulates during wakefulness, triggers sleep, and dissipates during sleep remains elusive. We explored a causal relationship between cellular synaptic strength and electroencephalography delta power indicating macro-level sleep pressure by developing a theoretical framework and a molecular tool to manipulate synaptic strength. The mathematical model predicted that increased synaptic strength promotes the neuronal "down state" and raises the delta power. Our molecular tool (synapse-targeted chemically induced translocation of Kalirin-7, SYNCit-K), which induces dendritic spine enlargement and synaptic potentiation through chemically induced translocation of protein Kalirin-7, demonstrated that synaptic potentiation of excitatory neurons in the prefrontal cortex (PFC) increases nonrapid eye movement sleep amounts and delta power. Thus, synaptic strength of PFC excitatory neurons dictates sleep pressure in mammals.

The neural oscillator model proposed by Matsuoka is a piecewise affine system that exhibits distinctive periodic solutions. Although such typical oscillation patterns have been widely studied, little is understood about the dynamics of convergence to certain fixed points and bifurcations between the periodic orbits and fixed points in this model. We performed fixed point analysis on a two-neuron version of the Matsuoka oscillator model, the result of which explains the mechanism of oscillation and the discontinuity-induced bifurcations such as subcritical/supercritical Hopf-like, homoclinic-like and grazing bifurcations. Furthermore, it provided theoretical predictions concerning a logarithmic oscillation-period scaling law and noise-induced oscillations observed around those bifurcations. These results are expected to underpin further investigations into oscillatory and transient neuronal activities concerning central pattern generators., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Cortical neurons exhibit highly variable responses over trials and time. Theoretical works posit that this variability arises potentially from chaotic network dynamics of recurrently connected neurons. Here, we demonstrate that chaotic neural dynamics, formed through synaptic learning, allow networks to perform sensory cue integration in a sampling-based implementation. We show that the emergent chaotic dynamics provide neural substrates for generating samples not only of a static variable but also of a dynamical trajectory, where generic recurrent networks acquire these abilities with a biologically plausible learning rule through trial and error. Furthermore, the networks generalize their experience in the stimulus-evoked samples to the inference without partial or all sensory information, which suggests a computational role of spontaneous activity as a representation of the priors as well as a tractable biological computation for marginal distributions. These findings suggest that chaotic neural dynamics may serve for the brain function as a Bayesian generative model., Competing Interests: Competing interests statement:The authors declare no competing interest.

The yield of a chemical reaction is obtained by solving its rate equation. This study introduces an approach for differentiating yields by utilizing the parameters of the rate equation, which is expressed as a first-order linear differential equation. The yield derivative for a specific pair of reactants and products is derived by mathematically expressing the rate constant matrix contraction method, which is a simple kinetic analysis method. The parameters of the rate equation are the Gibbs energies of the intermediates and transition states in the reaction path network used to formulate the rate equation. Thus, our approach for differentiating the yield allows a numerical evaluation of the contribution of energy variation to the yield for each intermediate and transition state in the reaction path network. In other words, a comparison of these values automatically extracts the factors affecting the yield from a complicated reaction path network consisting of numerous reaction paths and intermediates. This study verifies the behavior of the proposed approach through numerical experiments on the reaction path networks of a model system and the Rh-catalyzed hydroformylation reaction. Moreover, the possibility of using this approach for designing ligands in organometallic catalysts is discussed.

There are many modeling works that aim to explain people's behaviors that violate classical economic theories. However, these models often do not take into full account the multi-stage nature of real-life problems and people's tendency in solving complicated problems sequentially. In this work, we propose a descriptive decision-making model for multi-stage problems with perceived post-decision information. In the model, decisions are chosen based on an entity which we call the 'anticipated surprise'. The reference point is determined by the expected value of the possible outcomes, which we assume to be dynamically changing during the mental simulation of a sequence of events. We illustrate how our formalism can help us understand prominent economic paradoxes and gambling behaviors that involve multi-stage or sequential planning. We also discuss how neuroscience findings, like prediction error signals and introspective neuronal replay, as well as psychological theories like affective forecasting, are related to the features in our model. This provides hints for future experiments to investigate the role of these entities in decision-making., (© 2024. The Author(s).)

Sleep is considered to play an essential role in memory reorganization. Despite its importance, classical theoretical models did not focus on some sleep characteristics. Here, we review recent theoretical approaches investigating their roles in learning and discuss the possibility that non-rapid eye movement (NREM) sleep selectively consolidates memory, and rapid eye movement (REM) sleep reorganizes the representations of memories. We first review the possibility that slow waves during NREM sleep contribute to memory selection by using sequential firing patterns and the existence of up and down states. Second, we discuss the role of dreaming during REM sleep in developing neuronal representations. We finally discuss how to develop these points further, emphasizing the connections to experimental neuroscience and machine learning., Competing Interests: Declaration of competing interest We have no financial and personal relationships with other people or organizations that could inappropriately influence the work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adaptability to changing environments is one of the universal characteristics of living organisms. Because individual modes of adaptation are diverse, a unified understanding of these diverse modes is essential to comprehend adaptation. Adaptations can be categorized from at least two perspectives with respect to information. One is the passivity and activity of adaptation and the other is the type of information transmission. In Darwinian natural selection, organisms are selected among randomly generated traits under which individual organisms are passive in the sense that they do not process any environmental information. On the other hand, organisms can also adapt by sensing their environment and changing their traits. This is an active adaptation in that it makes use of environmental information. In terms of information transfer, adaptation through phenotypic heterogeneity, such as bacterial bet-hedging, is intragenerational in which traits are not passed on to the next generation. In contrast, adaptation through genetic diversity is intergenerational. The theory of population dynamics enables us to unify these various modes of adaptations and their properties can be analyzed qualitatively and quantitatively using techniques from quantitative genetics and information thermodynamics. In addition, such methods can be applied to situations where organisms can learn from past experiences and pass them on from generation to generation. In this work, we introduce the unified theory of biological adaptation based on population dynamics and show its potential applications to evaluate the fitness value of information and to analyze experimental lineage tree data. Finally, we discuss future perspectives for its development. This review article is an extended version of the Japanese article in SEIBUTSU BUTSURI Vol. 57, p. 287-290 (2017)., Competing Interests: We have nothing to declare for this review., (2023 © The Biophysical Society of Japan.)

Decentralized stochastic control (DSC) is a stochastic optimal control problem consisting of multiple controllers. DSC assumes that each controller is unable to accurately observe the target system and the other controllers. This setup results in two difficulties in DSC; one is that each controller has to memorize the infinite-dimensional observation history, which is not practical, because the memory of the actual controllers is limited. The other is that the reduction of infinite-dimensional sequential Bayesian estimation to finite-dimensional Kalman filter is impossible in general DSC, even for linear-quadratic-Gaussian (LQG) problems. In order to address these issues, we propose an alternative theoretical framework to DSC-memory-limited DSC (ML-DSC). ML-DSC explicitly formulates the finite-dimensional memories of the controllers. Each controller is jointly optimized to compress the infinite-dimensional observation history into the prescribed finite-dimensional memory and to determine the control based on it. Therefore, ML-DSC can be a practical formulation for actual memory-limited controllers. We demonstrate how ML-DSC works in the LQG problem. The conventional DSC cannot be solved except in the special LQG problems where the information the controllers have is independent or partially nested. We show that ML-DSC can be solved in more general LQG problems where the interaction among the controllers is not restricted.

Memory-limited partially observable stochastic control (ML-POSC) is the stochastic optimal control problem under incomplete information and memory limitation. To obtain the optimal control function of ML-POSC, a system of the forward Fokker-Planck (FP) equation and the backward Hamilton-Jacobi-Bellman (HJB) equation needs to be solved. In this work, we first show that the system of HJB-FP equations can be interpreted via Pontryagin's minimum principle on the probability density function space. Based on this interpretation, we then propose the forward-backward sweep method (FBSM) for ML-POSC. FBSM is one of the most basic algorithms for Pontryagin's minimum principle, which alternately computes the forward FP equation and the backward HJB equation in ML-POSC. Although the convergence of FBSM is generally not guaranteed in deterministic control and mean-field stochastic control, it is guaranteed in ML-POSC because the coupling of the HJB-FP equations is limited to the optimal control function in ML-POSC.

Choice information appears in multi-area brain networks mixed with sensory, motor, and cognitive variables. In the posterior cortex-traditionally implicated in decision computations-the presence, strength, and area specificity of choice signals are highly variable, limiting a cohesive understanding of their computational significance. Examining the mesoscale activity in the mouse posterior cortex during a visual task, we found that choice signals defined a decision variable in a low-dimensional embedding space with a prominent contribution along the ventral visual stream. Their subspace was near-orthogonal to concurrently represented sensory and motor-related activations, with modulations by task difficulty and by the animals' attention state. A recurrent neural network trained with animals' choices revealed an equivalent decision variable whose context-dependent dynamics agreed with that of the neural data. Our results demonstrated an independent, multi-area decision variable in the posterior cortex, controlled by task features and cognitive demands, possibly linked to contextual inference computations in dynamic animal-environment interactions., (© 2023. The Author(s).)

Complex networks often possess communities defined based on network connectivity. When dynamics undergo in a network, one can also consider dynamical communities, i.e., a group of nodes displaying a similar dynamical process. We have investigated both analytically and numerically the development of a dynamical community structure, where the community is referred to as a group of nodes synchronized in frequency, in networks of phase oscillators. We first demonstrate that using a few example networks, the community structure changes when network connectivity or interaction strength is varied. In particular, we found that community switching, i.e., a portion of oscillators change the group to which they synchronize, occurs for a range of parameters. We then propose a three-oscillator model: a bidirectional, weighted chain of three Kuramoto phase oscillators, as a theoretical framework for understanding the community formation and its variation. Our analysis demonstrates that the model shows a variety of partially synchronized patterns: oscillators with similar natural frequencies tend to synchronize for weak coupling, while tightly connected oscillators tend to synchronize for strong coupling. We obtain approximate expressions for the critical coupling strengths by employing a perturbative approach in a weak coupling regime and a geometric approach in strong coupling regimes. Moreover, we elucidate the bifurcation types of transitions between different patterns. Our theory might be useful for understanding the development of partially synchronized patterns in a wider class of complex networks than community structured networks.

A deep neural network is a good task solver, but it is difficult to make sense of its operation. People have different ideas about how to interpret its operation. We look at this problem from a new perspective where the interpretation of task solving is synthesized by quantifying how much and what previously unused information is exploited in addition to the information used to solve previous tasks. First, after learning several tasks, the network acquires several information partitions related to each task. We propose that the network then learns the minimal information partition that supplements previously learned information partitions to more accurately represent the input. This extra partition is associated with unconceptualized information that has not been used in previous tasks. We manage to identify what unconceptualized information is used and quantify the amount. To interpret how the network solves a new task, we quantify as meta-information how much information from each partition is extracted. We implement this framework with the variational information bottleneck technique. We test the framework with the MNIST and the CLEVR data set. The framework is shown to be able to compose information partitions and synthesize experience-dependent interpretation in the form of meta-information. This system progressively improves the resolution of interpretation upon new experience by converting a part of the unconceptualized information partition to a task-related partition. It can also provide a visual interpretation by imaging what is the part of previously unconceptualized information that is needed to solve a new task., (© 2022 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Slow waves during the non-rapid eye movement (NREM) sleep reflect the alternating up and down states of cortical neurons; global and local slow waves promote memory consolidation and forgetting, respectively. Furthermore, distinct spike-timing-dependent plasticity (STDP) operates in these up and down states. The contribution of different plasticity rules to neural information coding and memory reorganization remains unknown. Here, we show that optimal synaptic plasticity for information maximization in a cortical neuron model provides a unified explanation for these phenomena. The model indicates that the optimal synaptic plasticity is biased toward depression as the baseline firing rate increases. This property explains the distinct STDP observed in the up and down states. Furthermore, it explains how global and local slow waves predominantly potentiate and depress synapses, respectively, if the background firing rate of excitatory neurons declines with the spatial scale of waves as the model predicts. The model provides a unifying account of the role of NREM sleep, bridging neural information coding, synaptic plasticity, and memory reorganization., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

Optimal transport is a mathematical tool that has been a widely used to measure the distance between two probability distributions. To mitigate the cubic computational complexity of the vanilla formulation of the optimal transport problem, regularized optimal transport has received attention in recent years, which is a convex program to minimize the linear transport cost with an added convex regularizer. Sinkhorn optimal transport is the most prominent one regularized with negative Shannon entropy, leading to densely supported solutions, which are often undesirable in light of the interpretability of transport plans. In this paper, we report that a deformed entropy designed by q-algebra , a popular generalization of the standard algebra studied in Tsallis statistical mechanics, makes optimal transport solutions supported sparsely. This entropy with a deformation parameter q interpolates the negative Shannon entropy (q=1) and the squared 2-norm (q=0), and the solution becomes more sparse as q tends to zero. Our theoretical analysis reveals that a larger q leads to a faster convergence when optimized with the Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm. In summary, the deformation induces a trade-off between the sparsity and convergence speed.

Control problems with incomplete information and memory limitation appear in many practical situations. Although partially observable stochastic control (POSC) is a conventional theoretical framework that considers the optimal control problem with incomplete information, it cannot consider memory limitation. Furthermore, POSC cannot be solved in practice except in special cases. In order to address these issues, we propose an alternative theoretical framework, memory-limited POSC (ML-POSC). ML-POSC directly considers memory limitation as well as incomplete information, and it can be solved in practice by employing the technique of mean-field control theory. ML-POSC can generalize the linear-quadratic-Gaussian (LQG) problem to include memory limitation. Because estimation and control are not clearly separated in the LQG problem with memory limitation, the Riccati equation is modified to the partially observable Riccati equation, which improves estimation as well as control. Furthermore, we demonstrate the effectiveness of ML-POSC for a non-LQG problem by comparing it with the local LQG approximation.

Infant crying is a communicative behavior impaired in neurodevelopmental disorders (NDDs). Because advanced paternal age is a risk factor for NDDs, we performed computational approaches to evaluate how paternal age affected vocal communication and body weight development in C57BL/6 mouse offspring from young and aged fathers. Analyses of ultrasonic vocalization (USV) consisting of syllables showed that advanced paternal age reduced the number and duration of syllables, altered the syllable composition, and caused lower body weight gain in pups. Pups born to young fathers had convergent vocal characteristics with a rich repertoire, whereas those born to aged fathers exhibited more divergent vocal patterns with limited repertoire. Additional analyses revealed that some pups from aged fathers displayed atypical USV trajectories. Thus, our study indicates that advanced paternal age has a significant effect on offspring's vocal development. Our computational analyses are effective in characterizing altered individual diversity., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Memristive systems and devices are potentially available for implementing reservoir computing (RC) systems applied to pattern recognition. However, the computational ability of memristive RC systems depends on intertwined factors such as system architectures and physical properties of memristive elements, which complicates identifying the key factor for system performance. Here we develop a simulation platform for RC with memristor device networks, which enables testing different system designs for performance improvement. Numerical simulations show that the memristor-network-based RC systems can yield high computational performance comparable to that of state-of-the-art methods in three time series classification tasks. We demonstrate that the excellent and robust computation under device-to-device variability can be achieved by appropriately setting network structures, nonlinearity of memristors, and pre/post-processing, which increases the potential for reliable computation with unreliable component devices. Our results contribute to an establishment of a design guide for memristive reservoirs toward the realization of energy-efficient machine learning hardware., (© 2022. The Author(s).)

Our ability to perceive a stable visual world in the presence of continuous movements of the body, head, and eyes has puzzled researchers in the neuroscience field for a long time. We reformulated this problem in the context of hierarchical convolutional neural networks (CNNs)-whose architectures have been inspired by the hierarchical signal processing of the mammalian visual system-and examined perceptual stability as an optimization process that identifies image-defining features for accurate image classification in the presence of movements. Movement signals, multiplexed with visual inputs along overlapping convolutional layers, aided classification invariance of shifted images by making the classification faster to learn and more robust relative to input noise. Classification invariance was reflected in activity manifolds associated with image categories emerging in late CNN layers and with network units acquiring movement-associated activity modulations as observed experimentally during saccadic eye movements. Our findings provide a computational framework that unifies a multitude of biological observations on perceptual stability under optimality principles for image classification in artificial neural networks., Competing Interests: The authors have declared that no competing interests exist.

Selecting diverse molecules from unexplored areas of chemical space is one of the most important tasks for discovering novel molecules and reactions. This paper proposes a new approach for selecting a subset of diverse molecules from a given molecular list by using two existing techniques studied in machine learning and mathematical optimization: graph neural networks (GNNs) for learning vector representation of molecules and a diverse-selection framework called submodular function maximization. Our method, called SubMo-GNN, first trains a GNN with property prediction tasks, and then the trained GNN transforms molecular graphs into molecular vectors, which capture both properties and structures of molecules. Finally, to obtain a subset of diverse molecules, we define a submodular function, which quantifies the diversity of molecular vectors, and find a subset of molecular vectors with a large submodular function value. This can be done efficiently by using the greedy algorithm, and the diversity of selected molecules measured by the submodular function value is mathematically guaranteed to be at least 63% of that of an optimal selection. We also introduce a new evaluation criterion to measure the diversity of selected molecules based on molecular properties. Computational experiments confirm that our SubMo-GNN successfully selects diverse molecules from the QM9 dataset regarding the property-based criterion, while performing comparably to existing methods regarding standard structure-based criteria. We also demonstrate that SubMo-GNN with a GNN trained on the QM9 dataset can select diverse molecules even from other MoleculeNet datasets whose domains are different from the QM9 dataset. The proposed method enables researchers to obtain diverse sets of molecules for discovering new molecules and novel chemical reactions, and the proposed diversity criterion is useful for discussing the diversity of molecular libraries from a new property-based perspective., (© 2022. The Author(s).)

Conventional theories assume that long-term information storage in the brain is implemented by modifying synaptic efficacy. Recent experimental findings challenge this view by demonstrating that dendritic spine sizes, or their corresponding synaptic weights, are highly volatile even in the absence of neural activity. Here, we review previous computational works on the roles of these intrinsic synaptic dynamics. We first present the possibility for neuronal networks to sustain stable performance in their presence, and we then hypothesize that intrinsic dynamics could be more than mere noise to withstand, but they may improve information processing in the brain., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

During perceptual decision-making, the brain encodes the upcoming decision and the stimulus information in a mixed representation. Paradigms suitable for studying decision computations in isolation rely on stimulus comparisons, with choices depending on relative rather than absolute properties of the stimuli. The adoption of tasks requiring relative perceptual judgments in mice would be advantageous in view of the powerful tools available for the dissection of brain circuits. However, whether and how mice can perform a relative visual discrimination task has not yet been fully established. Here, we show that mice can solve a complex orientation discrimination task in which the choices are decoupled from the orientation of individual stimuli. Moreover, we demonstrate a typical discrimination acuity of 9°, challenging the common belief that mice are poor visual discriminators. We reached these conclusions by introducing a probabilistic choice model that explained behavioral strategies in 40 mice and demonstrated that the circularity of the stimulus space is an additional source of choice variability for trials with fixed difficulty. Furthermore, history biases in the model changed with task engagement, demonstrating behavioral sensitivity to the availability of cognitive resources. In conclusion, our results reveal that mice adopt a diverse set of strategies in a task that decouples decision-relevant information from stimulus-specific information, thus demonstrating their usefulness as an animal model for studying neural representations of relative categories in perceptual decision-making research., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Visually guided behaviors depend on the activity of cortical networks receiving visual inputs and transforming these signals to guide appropriate actions. However, non-retinal inputs, carrying motor signals as well as cognitive and attentional modulatory signals, also activate these cortical regions. How these networks integrate coincident signals ensuring reliable visual behaviors is poorly understood. In this study, we observe neural responses in the dorsal-parietal cortex of mice during a visual discrimination task driven by visual stimuli and movements. We find that visual and motor signals interact according to two mechanisms: divisive normalization and separation of responses. Interactions are contextually modulated by the animal's state of sustained attention, which amplifies visual and motor signals and increases their discriminability in a low-dimensional space of neural activations. These findings reveal computational principles operating in dorsal-parietal networks that enable separation of incoming signals for reliable visually guided behaviors during interactions with the environment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the brain, most synapses are formed on minute protrusions known as dendritic spines. Unlike their artificial intelligence counterparts, spines are not merely tuneable memory elements: they also embody algorithms that implement the brain's ability to learn from experience and cope with new challenges. Importantly, they exhibit structural dynamics that depend on activity, excitatory input and inhibitory input (synaptic plasticity or 'extrinsic' dynamics) and dynamics independent of activity ('intrinsic' dynamics), both of which are subject to neuromodulatory influences and reinforcers such as dopamine. Here we succinctly review extrinsic and intrinsic dynamics, compare these with parallels in machine learning where they exist, describe the importance of intrinsic dynamics for memory management and adaptation, and speculate on how disruption of extrinsic and intrinsic dynamics may give rise to mental disorders. Throughout, we also highlight algorithmic features of spine dynamics that may be relevant to future artificial intelligence developments.

For many years, a combination of principal component analysis (PCA) and independent component analysis (ICA) has been used for blind source separation (BSS). However, it remains unclear why these linear methods work well with real-world data that involve nonlinear source mixtures. This work theoretically validates that a cascade of linear PCA and ICA can solve a nonlinear BSS problem accurately-when the sensory inputs are generated from hidden sources via nonlinear mappings with sufficient dimensionality. Our proposed theorem, termed the asymptotic linearization theorem, theoretically guarantees that applying linear PCA to the inputs can reliably extract a subspace spanned by the linear projections from every hidden source as the major components-and thus projecting the inputs onto their major eigenspace can effectively recover a linear transformation of the hidden sources. Then subsequent application of linear ICA can separate all the true independent hidden sources accurately. Zero-element-wise-error nonlinear BSS is asymptotically attained when the source dimensionality is large and the input dimensionality is sufficiently larger than the source dimensionality. Our proposed theorem is validated analytically and numerically. Moreover, the same computation can be performed by using Hebbian-like plasticity rules, implying the biological plausibility of this nonlinear BSS strategy. Our results highlight the utility of linear PCA and ICA for accurately and reliably recovering nonlinearly mixed sources and suggest the importance of employing sensors with sufficient dimensionality to identify true hidden sources of real-world data., (© 2021 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

In phase I trials, the main goal is to identify a maximum tolerated dose under an assumption of monotonicity in dose-response relationships. On the other hand, such monotonicity is no longer applied to biologic agents because a different mode of action from that of cytotoxic agents potentially draws unimodal or flat dose-efficacy curves. Therefore, biologic agents require an optimal dose that provides a sufficient efficacy rate under an acceptable toxicity rate instead of a maximum tolerated dose. Many trials incorporate both toxicity and efficacy data, and drugs with a variety of modes of actions are increasingly being developed; thus, optimal dose estimation designs have been receiving increased attention. Although numerous authors have introduced parametric model-based designs, it is not always appropriate to apply strong assumptions in dose-response relationships. We propose a new design based on a Bayesian optimization framework for identifying optimal doses for biologic agents in phase I/II trials. Our proposed design models dose-response relationships via nonparametric models utilizing a Gaussian process prior, and the uncertainty of estimates is considered in the dose selection process. We compared the operating characteristics of our proposed design against those of three other designs through simulation studies. These include an expansion of Bayesian optimal interval design, the parametric model-based EffTox design, and the isotonic design. In simulations, our proposed design performed well and provided results that were more stable than those from the other designs, in terms of the accuracy of optimal dose estimations and the percentage of correct recommendations., (© 2020 John Wiley & Sons Ltd.)

Decentralized partially observable Markov decision process (DEC-POMDP) models sequential decision making problems by a team of agents. Since the planning of DEC-POMDP can be interpreted as the maximum likelihood estimation for the latent variable model, DEC-POMDP can be solved by the EM algorithm. However, in EM for DEC-POMDP, the forward-backward algorithm needs to be calculated up to the infinite horizon, which impairs the computational efficiency. In this paper, we propose the Bellman EM algorithm (BEM) and the modified Bellman EM algorithm (MBEM) by introducing the forward and backward Bellman equations into EM. BEM can be more efficient than EM because BEM calculates the forward and backward Bellman equations instead of the forward-backward algorithm up to the infinite horizon. However, BEM cannot always be more efficient than EM when the size of problems is large because BEM calculates an inverse matrix. We circumvent this shortcoming in MBEM by calculating the forward and backward Bellman equations without the inverse matrix. Our numerical experiments demonstrate that the convergence of MBEM is faster than that of EM.

The chemotactic network of Escherichia coli has been studied extensively both biophysically and information theoretically. Nevertheless, connection between these two aspects is still elusive. In this work, we report such a connection. We derive an optimal filtering dynamics under the assumption that E. coli's sensory system optimally infers the binary information whether it is swimming up or down along an exponential ligand gradient from noisy sensory signals. Then we show that a standard biochemical model of the chemotactic network is mathematically equivalent to this information-theoretically optimal dynamics. Moreover, we demonstrate that an experimentally observed nonlinear response relation can be reproduced from the optimal dynamics. These results suggest that the biochemical network of E. coli chemotaxis is designed to optimally extract the binary information along an exponential gradient in a noisy condition.