Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique, offering a potential alternative to pharmacological treatments for psychiatric and neurological disorders. While functional analysis has been instrumental in characterizing the TUS effects, understanding its indirect influence across the network remains challenging. Here, we developed a whole-brain model to represent functional changes as measured by fMRI, enabling us to investigate how TUS-induced effects propagate throughout the brain with increasing stimulus intensity. We implemented two mechanisms: one based on anatomical distance and another on broadcasting dynamics, to explore plasticity-driven changes in specific brain regions. Finally, we highlighted the role of higher-order functional interactions in localizing spatial effects of off-line TUS at two target areas-the right thalamus and inferior frontal cortex-revealing distinct patterns of functional reorganization. This work lays the foundation for mechanistic insights and predictive models of TUS, advancing its potential clinical applications.

Computational researchers often collaborate with experimental researchers, but what about starting their own experimental lab alongside computational work?While collaborating with experimental colleagues might be beneficial, maybe you have ideas for experiments that have not been done or maybe you want to measure parameters that would be useful for models, but that have not been obtained in experimental studies?Or maybe you want to simply test whether the predictions from your computational models are true for biological systems?The move to experimental studies might occur at different career stages.After completing a theoretical or computational undergraduate degree or PhD, one might move into an experimental lab.However, moving into experimental work becomes more challenging when moving from a career and track record that is solely based on computational research.Here, we share Ten Simple Rules in an attempt to make this transition feasible at later career stages.Moving to experimental studies can be daunting for several reasons.Managing an experimental lab is different from managing a computational lab.While data exists in cyberspace, devices in the real-world need lab space, maintenance, and technical support.Also, experiments involve ethics proposals and dealing with animals or with human participants.Finally, moving to experimental research can elicit discouraging thoughts such as "How will I get funding without a track record in experimental research," "How will I manage to start my career from scratch again," and "How will I find time to learn what is needed?".Doing experimental research has a steep learning curve and is a major commitment; it is not right for everyone.However, combining computational and experimental research in your lab can be extremely rewarding.Hodgkin and Huxley not only performed mathematical modelling of neural activity (action potentials), but also developed experiments to get quantitative data about the phenomenon [1].It is this unique combination of modelling and experiments that led to insights about action potential and ultimately led to them being awarded the Nobel Prize in Physiology or Medicine (for 10 other ways to win the Nobel Prize, see [2]).So, you have made the decision to move into experimental research.Now what?Rule 1: Link up with experimentalistsAU : Pleaseconfirmthatallheadinglevelsare If you are thinking about setting up an experimental lab, it is crucial to establish links with other experimental groups to learn about techniques and lab organisation.You might already have research collaborations with experimental labs that can give you information about what equipment to buy and what processes are in place for planning experimental studies.After closely collaborating with experimental researchers, it is crucial to spend actual time in their lab-not just observing but participating in experiments.Spending more time will give

Significant research has investigated synchronisation in brain networks, but the bulk of this work has explored the contribution of brain networks at the macroscale. Here we explore the effects of changing network topology on functional dynamics in spatially constrained random networks representing mesoscale neocortex. We use the Kuramoto model to simulate network dynamics and explore synchronisation and critical dynamics of the system as a function of topology in randomly generated networks with a distance-related wiring probability and no preferential attachment term. We show networks which predominantly make short-distance connections smooth out the critical coupling point and show much greater metastability, resulting in a wider range of coupling strengths demonstrating critical dynamics and metastability. We show the emergence of cluster synchronisation in these geometrically-constrained networks with functional organisation occurring along structural connections that minimise the participation coefficient of the cluster. We show that these cohorts of internally synchronised nodes also behave en masse as weakly coupled nodes and show intra-cluster desynchronisation and resynchronisation events related to inter-cluster interaction. While cluster synchronisation appears crucial to healthy brain function, it may also be pathological if it leads to unbreakable local synchronisation which may happen at extreme topologies, with implications for epilepsy research, wider brain function and other domains such as social networks.

MOTIVATION: Agent-based modeling is an indispensable tool for studying complex biological systems. However, existing simulation platforms do not always take full advantage of modern hardware and often have a field-specific software design. RESULTS: We present a novel simulation platform called BioDynaMo that alleviates both of these problems. BioDynaMo features a modular and high-performance simulation engine. We demonstrate that BioDynaMo can be used to simulate use cases in: neuroscience, oncology and epidemiology. For each use case, we validate our findings with experimental data or an analytical solution. Our performance results show that BioDynaMo performs up to three orders of magnitude faster than the state-of-the-art baselines. This improvement makes it feasible to simulate each use case with one billion agents on a single server, showcasing the potential BioDynaMo has for computational biology research. AVAILABILITY AND IMPLEMENTATION: BioDynaMo is an open-source project under the Apache 2.0 license and is available at www.biodynamo.org. Instructions to reproduce the results are available in the supplementary information. SUPPLEMENTARY INFORMATION: Available at https://doi.org/10.5281/zenodo.5121618.

MOTIVATION: Flux balance analysis (FBA) based bilevel optimization has been a great success in redesigning metabolic networks for biochemical overproduction. To date, many computational approaches have been developed to solve the resulting bilevel optimization problems. However, most of them are of limited use due to biased optimality principle, poor scalability with the size of metabolic networks, potential numeric issues or low quantity of design solutions in a single run. RESULTS: Here, we have employed a network interdiction model free of growth optimality assumptions, a special case of bilevel optimization, for computational strain design and have developed a hybrid Benders algorithm (HBA) that deals with complicating binary variables in the model, thereby achieving high efficiency without numeric issues in search of best design strategies. More importantly, HBA can list solutions that meet users' production requirements during the search, making it possible to obtain numerous design strategies at a small runtime overhead (typically ∼1 h, e.g. studied in this article). AVAILABILITY AND IMPLEMENTATION: Source code implemented in the MATALAB Cobratoolbox is freely available at https://github.com/chang88ye/NIHBA. CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Simulations of neural networks can be used to study the direct effect of internal or external changes on brain dynamics. However, some changes are not immediate but occur on the timescale of weeks, months, or years. Examples include effects of strokes, surgical tissue removal, or traumatic brain injury but also gradual changes during brain development. Simulating network activity over a long time, even for a small number of nodes, is a computational challenge. Here, we model a coupled network of human brain regions with a modified Wilson-Cowan model representing dynamics for each region and with synaptic plasticity adjusting connection weights within and between regions. Using strategies ranging from different models for plasticity, vectorization and a different differential equation solver setup, we achieved one second runtime for one second biological time.

Population-based evolutionary algorithms have great potential to handle multiobjective optimisation problems . However, the performance of these algorithms depends largely on problem characteristics. There is a need to improve these algorithms for wide applicability. References, often specified by the decision maker’s preference in different forms, are very effective to boost the performance of algorithms. This paper proposes a novel framework for effective use of references to strengthen algorithms. This framework considers references as search targets which can be adjusted based on the information collected during the search. The proposed framework is combined with new strategies, such as reference adaptation and adaptive local mating, to solve different types of problems. The proposed algorithm is compared with state-of-the-arts on a wide range of problems with diverse characteristics. The comparison and extensive sensitivity analysis demonstrate that the proposed algorithm is competitive and robust across different types of problems studied in this paper.

Dynamic multiobjective optimization (DMO) has gained increasing attention in recent years. Test problems are of great importance in order to facilitate the development of advanced algorithms that can handle dynamic environments well. However, many of the existing dynamic multiobjective test problems have not been rigorously constructed and analyzed, which may induce some unexpected bias when they are used for algorithmic analysis. In this paper, some of these biases are identified after a review of widely used test problems. These include poor scalability of objectives and, more important, problematic overemphasis of static properties rather than dynamics making it difficult to draw accurate conclusion about the strengths and weaknesses of the algorithms studied. A diverse set of dynamics and features is then highlighted that a good test suite should have. We further develop a scalable continuous test suite, which includes a number of dynamics or features that have been rarely considered in literature but frequently occur in real life. It is demonstrated with empirical studies that the proposed test suite is more challenging to the DMO algorithms found in the literature. The test suite can also test algorithms in ways that existing test suites cannot.

Dynamic multiobjective optimisation deals with multiobjective problems whose objective functions, search spaces, or constraints are time-varying during the optimisation process. Due to wide presence in real-world applications, dynamic multiobjective problems (DMOPs) have been increasingly studied in recent years. Whilst most studies concentrated on DMOPs with only two objectives, there is little work on more objectives. This paper presents an empirical investigation of evolutionary algorithms for three-objective dynamic problems. Experimental studies show that all the evolutionary algorithms tested in this paper encounter performance degradedness to some extent. Amongst these algorithms, the multipopulation based change handling mechanism is generally more robust for a larger number of objectives, but has difficulty in deal with time-varying deceptive characteristics.

Multiobjective optimisation in dynamic environments is challenging due to the presence of dynamics in the problems in question. Whilst much progress has been made in benchmarks and algorithm design for dynamic multiobjective optimisation, there is a lack of work on the detectability of environmental changes and how this affects the performance of evolutionary algorithms. This is not intentionally left blank but due to the unavailability of suitable test cases to study. To bridge the gap, this work presents several scenarios where environmental changes are less likely to be detected. Our experimental studies suggest that the less detectable environments pose a big challenge to evolutionary algorithms.

Focal seizures are episodes of pathological brain activity that appear to arise from a localised area of the brain. The onset patterns of focal seizure activity have been studied intensively, and they have largely been distinguished into two types-low amplitude fast oscillations (LAF), or high amplitude spikes (HAS). Here we explore whether these two patterns arise from fundamentally different mechanisms. Here, we use a previously established computational model of neocortical tissue, and validate it as an adequate model using clinical recordings of focal seizures. We then reproduce the two onset patterns in their most defining properties and investigate the possible mechanisms underlying the different focal seizure onset patterns in the model. We show that the two patterns are associated with different mechanisms at the spatial scale of a single ECoG electrode. The LAF onset is initiated by independent patches of localised activity, which slowly invade the surrounding tissue and coalesce over time. In contrast, the HAS onset is a global, systemic transition to a coexisting seizure state triggered by a local event. We find that such a global transition is enabled by an increase in the excitability of the "healthy" surrounding tissue, which by itself does not generate seizures, but can support seizure activity when incited. In our simulations, the difference in surrounding tissue excitability also offers a simple explanation of the clinically reported difference in surgical outcomes. Finally, we demonstrate in the model how changes in tissue excitability could be elucidated, in principle, using active stimulation. Taken together, our modelling results suggest that the excitability of the tissue surrounding the seizure core may play a determining role in the seizure onset pattern, as well as in the surgical outcome.

In this paper, we propose a novel algorithmic solution to the vehicle relocation problem in free floating carsharing systems. In this type of systems, a set of vehicles is distributed in a city and made available for customers. After a customer rents a vehicle for a period of time, he/she returns it at any place within the operation area of the vehicle operator. Such type of carsharing systems can quickly become imbalanced in a sense that many vehicles might be left in areas with low customers demand while high-demand areas might contain very few vehicles. Therefore, a relocation process is required to retain the balance by transporting vehicles from low to high-demand areas. The relocation is done by a set of workers sharing a shuttle. We consider maximizing the number of relocated vehicles, that can be done within a given time frame, and minimizing the travel duration of the shuttle. The problem is modeled as a generalization of the pickup and delivery problem which is an NP-hard optimization problem. To solve the problem, we propose an evolutionary algorithm which has been tested on real world problem instances under different settings. Experimentation results showed that the algorithm was able to successfully solve the problem and cope with the different problems settings in reasonable time.

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder resulting in disruptive seizures. In the case of drug resistant epilepsy resective surgery is often considered. This is a procedure hampered by unpredictable success rates, with many patients continuing to have seizures even after surgery. In this study we apply a computational model of epilepsy to patient specific structural connectivity derived from diffusion tensor imaging (DTI) of 22 individuals with left TLE and 39 healthy controls. We validate the model by examining patient-control differences in simulated seizure onset time and network location. We then investigate the potential of the model for surgery prediction by performing in silico surgical resections, removing nodes from patient networks and comparing seizure likelihood post-surgery to pre-surgery simulations. We find that, first, patients tend to transit from non-epileptic to epileptic states more often than controls in the model. Second, regions in the left hemisphere (particularly within temporal and subcortical regions) that are known to be involved in TLE are the most frequent starting points for seizures in patients in the model. In addition, our analysis also implicates regions in the contralateral and frontal locations which may play a role in seizure spreading or surgery resistance. Finally, the model predicts that patient-specific surgery (resection areas chosen on an individual, model-prompted, basis and not following a predefined procedure) may lead to better outcomes than the currently used routine clinical procedure. Taken together this work provides a first step towards patient specific computational modelling of epilepsy surgery in order to inform treatment strategies in individuals.

Distributed systems such as the Internet and wireless sensor networks must provide a high degree of resilience against errors and attacks. Besides steps that increase reliability of data and resources of the network, the topology structure itself plays a crucial role in the efficacy of the fault-tolerance behavior. The network topology is a supportive factor to reduce or avoid malfunction behavior of the system after a strike on a strategic node or a random failure of a node. For a self-organizing topology with numerous nodes, it is necessary to have a local fault tolerance measure instead of collecting information of the entire network to adjust the topology locally when needed. The local clustering coefficient determines the degree of the connectedness of the node's neighbors. The correlation between the clustering coefficient and fault tolerance is an open research problem. In this paper, we propose the clustering coefficient as a local metric for fault tolerance, in particular for wireless sensor networks. We describe how to increase the clustering coefficient by (a) exclusively adding and (b) exclusively removing links to a wireless sensor network topology. Simulation results indicate that the clustering coefficient is correlated to the fault tolerance of the system.

The nematode Caenorhabditis elegans, with information on neural connectivity, three-dimensional position and cell linage, provides a unique system for understanding the development of neural networks. Although C. elegans has been widely studied in the past, we present the first statistical study from a developmental perspective, with findings that raise interesting suggestions on the establishment of long-distance connections and network hubs. Here, we analyze the neuro-development for temporal and spatial features, using birth times of neurons and their three-dimensional positions. Comparisons of growth in C. elegans with random spatial network growth highlight two findings relevant to neural network development. First, most neurons which are linked by long-distance connections are born around the same time and early on, suggesting the possibility of early contact or interaction between connected neurons during development. Second, early-born neurons are more highly connected (tendency to form hubs) than later-born neurons. This indicates that the longer time frame available to them might underlie high connectivity. Both outcomes are not observed for random connection formation. The study finds that around one-third of electrically coupled long-range connections are late forming, raising the question of what mechanisms are involved in ensuring their accuracy, particularly in light of the extremely invariant connectivity observed in C. elegans. In conclusion, the sequence of neural network development highlights the possibility of early contact or interaction in securing long-distance and high-degree connectivity.

Complex networks from domains like Biology or Sociology are present in many e-Science data sets. Dealing with networks can often form a workflow bottleneck as several related algorithms are computationally hard. One example is detecting characteristic patterns or "network motifs" - a problem involving subgraph mining and graph isomorphism. This paper provides a review and runtime comparison of current motif detection algorithms in the field. We present the strategies and the corresponding algorithms in pseudo-code yielding a framework for comparison. We categorize the algorithms outlining the main differences and advantages of each strategy. We finally implement all strategies in a common platform to allow a fair and objective efficiency comparison using a set of benchmark networks. We hope to inform the choice of strategy and critically discuss future improvements in motif detection.

It has been suggested that neural systems across several scales of organization show optimal component placement, in which any spatial rearrangement of the components would lead to an increase of total wiring. Using extensive connectivity datasets for diverse neural networks combined with spatial coordinates for network nodes, we applied an optimization algorithm to the network layouts, in order to search for wire-saving component rearrangements. We found that optimized component rearrangements could substantially reduce total wiring length in all tested neural networks. Specifically, total wiring among 95 primate (Macaque) cortical areas could be decreased by 32%, and wiring of neuronal networks in the nematode Caenorhabditis elegans could be reduced by 48% on the global level, and by 49% for neurons within frontal ganglia. Wiring length reductions were possible due to the existence of long-distance projections in neural networks. We explored the role of these projections by comparing the original networks with minimally rewired networks of the same size, which possessed only the shortest possible connections. In the minimally rewired networks, the number of processing steps along the shortest paths between components was significantly increased compared to the original networks. Additional benchmark comparisons also indicated that neural networks are more similar to network layouts that minimize the length of processing paths, rather than wiring length. These findings suggest that neural systems are not exclusively optimized for minimal global wiring, but for a variety of factors including the minimization of processing steps.