Search Algorithms as a Framework for the Optimization of Drug Combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms—originally developed for digital communication—modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs using only one-third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6–9 interventions in 80–90% of tests, compared with 15–30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.     

Unconscious mental imagery

Historically, mental imagery has been defined as an experiential state—as something necessarily conscious. But most behavioural or neuroimaging experiments on mental imagery—including the most famous ones—do not actually take the conscious experience of the subject into consideration. Further, recent research highlights that there are very few behavioural or neural differences between conscious and unconscious mental imagery. I argue that treating mental imagery as not necessarily conscious (as potentially unconscious) would bring much needed explanatory unification to mental imagery research. It would also help us to reassess some of the recent aphantasia findings inasmuch as at least some subjects with aphantasia would be best described as having unconscious mental imagery.This article is part of the theme issue ‘Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation’.     

Hippocampus Is Place of Interaction between Unconscious and Conscious Memories

Recent evidence suggests that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus—the key structure also recruited for conscious relational (episodic) memory. If the hippocampus subserves both conscious and unconscious relational encoding/retrieval, one would expect the hippocampus to be place of unconscious-conscious interactions during memory retrieval. We tested this hypothesis in an fMRI experiment probing the interaction between the unconscious and conscious retrieval of face-associated information. For the establishment of unconscious relational memories, we presented subliminal (masked) combinations of unfamiliar faces and written occupations (“actor” or “politician”). At test, we presented the former subliminal faces, but now supraliminally, as cues for the reactivation of the unconsciously associated occupations. We hypothesized that unconscious reactivation of the associated occupation—actor or politician—would facilitate or inhibit the subsequent conscious retrieval of a celebrity’s occupation, which was also actor or politician. Depending on whether the reactivated unconscious occupation was congruent or incongruent to the celebrity’s occupation, we expected either quicker or delayed conscious retrieval process. Conscious retrieval was quicker in the congruent relative to a neutral baseline condition but not delayed in the incongruent condition. fMRI data collected during subliminal face-occupation encoding confirmed previous evidence that the hippocampus was interacting with neocortical storage sites of semantic knowledge to support relational encoding. fMRI data collected at test revealed that the facilitated conscious retrieval was paralleled by deactivations in the hippocampus and neocortical storage sites of semantic knowledge. We assume that the unconscious reactivation has pre-activated overlapping relational representations in the hippocampus reducing the neural effort for conscious retrieval. This finding supports the notion of synergistic interactions between conscious and unconscious relational memories in a common, cohesive hippocampal-neocortical memory space.     

Measuring the repertoire of age-related behavioral changes in Drosophila melanogaster

Aging affects almost all aspects of an organism—its morphology, its physiology, its behavior. Isolating which biological mechanisms are regulating these changes, however, has proven difficult, potentially due to our inability to characterize the full repertoire of an animal’s behavior across the lifespan. Using data from fruit flies (D. melanogaster) we measure the full repertoire of behaviors as a function of age. We observe a sexually dimorphic pattern of changes in the behavioral repertoire during aging. Although the stereotypy of the behaviors and the complexity of the repertoire overall remains relatively unchanged, we find evidence that the observed alterations in behavior can be explained by changing the fly’s overall energy budget, suggesting potential connections between metabolism, aging, and behavior.     

Task-induced neural covariability as a signature of approximate Bayesian learning and inference

Perception is often characterized computationally as an inference process in which uncertain or ambiguous sensory inputs are combined with prior expectations. Although behavioral studies have shown that observers can change their prior expectations in the context of a task, robust neural signatures of task-specific priors have been elusive. Here, we analytically derive such signatures under the general assumption that the responses of sensory neurons encode posterior beliefs that combine sensory inputs with task-specific expectations. Specifically, we derive predictions for the task-dependence of correlated neural variability and decision-related signals in sensory neurons. The qualitative aspects of our results are parameter-free and specific to the statistics of each task. The predictions for correlated variability also differ from predictions of classic feedforward models of sensory processing and are therefore a strong test of theories of hierarchical Bayesian inference in the brain. Importantly, we find that Bayesian learning predicts an increase in so-called “differential correlations” as the observer’s internal model learns the stimulus distribution, and the observer’s behavioral performance improves. This stands in contrast to classic feedforward encoding/decoding models of sensory processing, since such correlations are fundamentally information-limiting. We find support for our predictions in data from existing neurophysiological studies across a variety of tasks and brain areas. Finally, we show in simulation how measurements of sensory neural responses can reveal information about a subject’s internal beliefs about the task. Taken together, our results reinterpret task-dependent sources of neural covariability as signatures of Bayesian inference and provide new insights into their cause and their function.     

What Would Jaws Do? The Tyranny of Film and the Relationship between Gaze and Higher-Level Narrative Film Comprehension

What is the relationship between film viewers’ eye movements and their film comprehension? Typical Hollywood movies induce strong attentional synchrony—most viewers look at the same things at the same time. Thus, we asked whether film viewers’ eye movements would differ based on their understanding—the mental model hypothesis—or whether any such differences would be overwhelmed by viewers’ attentional synchrony—the tyranny of film hypothesis. To investigate this question, we manipulated the presence/absence of prior film context and measured resulting differences in film comprehension and eye movements. Viewers watched a 12-second James Bond movie clip, ending just as a critical predictive inference should be drawn that Bond’s nemesis, “Jaws,” would fall from the sky onto a circus tent. The No-context condition saw only the 12-second clip, but the Context condition also saw the preceding 2.5 minutes of the movie before seeing the critical 12-second portion. Importantly, the Context condition viewers were more likely to draw the critical inference and were more likely to perceive coherence across the entire 6 shot sequence (as shown by event segmentation), indicating greater comprehension. Viewers’ eye movements showed strong attentional synchrony in both conditions as compared to a chance level baseline, but smaller differences between conditions. Specifically, the Context condition viewers showed slightly, but significantly, greater attentional synchrony and lower cognitive load (as shown by fixation probability) during the critical first circus tent shot. Thus, overall, the results were more consistent with the tyranny of film hypothesis than the mental model hypothesis. These results suggest the need for a theory that encompasses processes from the perception to the comprehension of film.     

The Anterior Insula Tracks Behavioral Entropy during an Interpersonal Competitive Game

In competitive situations, individuals need to adjust their behavioral strategy dynamically in response to their opponent’s behavior. In the present study, we investigated the neural basis of how individuals adjust their strategy during a simple, competitive game of matching pennies. We used entropy as a behavioral index of randomness in decision-making, because maximizing randomness is thought to be an optimal strategy in the game, according to game theory. While undergoing functional magnetic resonance imaging (fMRI), subjects played matching pennies with either a human or computer opponent in each block, although in reality they played the game with the same computer algorithm under both conditions. The winning rate of each block was also manipulated. Both the opponent (human or computer), and the winning rate, independently affected subjects’ block-wise entropy during the game. The fMRI results revealed that activity in the bilateral anterior insula was positively correlated with subjects’ (not opponent’s) behavioral entropy during the game, which indicates that during an interpersonal competitive game, the anterior insula tracked how uncertain subjects’ behavior was, rather than how uncertain subjects felt their opponent''s behavior was. Our results suggest that intuitive or automatic processes based on somatic markers may be a key to optimally adjusting behavioral strategies in competitive situations.     

Circumpolar Genetic Structure and Recent Gene Flow of Polar Bears: A Reanalysis

Recently, an extensive study of 2,748 polar bears (Ursus maritimus) from across their circumpolar range was published in PLOS ONE, which used microsatellites and mitochondrial haplotypes to apparently show altered population structure and a dramatic change in directional gene flow towards the Canadian Archipelago—an area believed to be a future refugium for polar bears as their southernmost habitats decline under climate change. Although this study represents a major international collaborative effort and promised to be a baseline for future genetics work, methodological shortcomings and errors of interpretation undermine some of the study’s main conclusions. Here, we present a reanalysis of this data in which we address some of these issues, including: (1) highly unbalanced sample sizes and large amounts of systematically missing data; (2) incorrect calculation of F_ST and of significance levels; (3) misleading estimates of recent gene flow resulting from non-convergence of the program BayesAss. In contrast to the original findings, in our reanalysis we find six genetic clusters of polar bears worldwide: the Hudson Bay Complex, the Western and Eastern Canadian Arctic Archipelago, the Western and Eastern Polar Basin, and—importantly—we reconfirm the presence of a unique and possibly endangered cluster of bears in Norwegian Bay near Canada’s expected last sea-ice refugium. Although polar bears’ abundance, distribution, and population structure will certainly be negatively affected by ongoing—and increasingly rapid—loss of Arctic sea ice, these genetic data provide no evidence of strong directional gene flow in response to recent climate change.     

Nutritional biology: a neglected basic discipline of nutritional science

On the basis of a scientific-philosophical analysis, this paper tries to show that the approaches in current nutritional science—including its subdisciplines which focus on molecular aspects—are predominantly application-oriented. This becomes particularly evident through a number of conceptual problems characterized by the triad of ‘dearth of theoretical foundation,’ ‘particularist research questions,’ and ‘reductionist understanding of nutrition.’ The thesis presented here is that an interpretive framework based on nutritional biology is able to shed constructive light on the fundamental problems of nutritional science. In this context, the establishment of ‘nutritional biology’ as a basic discipline in research and education would be a first step toward recognizing the phenomenon of ‘nutrition’ as an oecic process as a special case of an organism–environment interaction. Modern nutritional science should be substantively grounded on ecological—and therefore systems biology as well as organismic—principles. The aim of nutritional biology, then, should be to develop near-universal ‘law statements’ in nutritional science—a task which presents a major challenge for the current science system.     

Tuned inhibition in perceptual decision-making circuits can explain seemingly suboptimal confidence behavior

Current dominant views hold that perceptual confidence reflects the probability that a decision is correct. Although these views have enjoyed some empirical support, recent behavioral results indicate that confidence and the probability of being correct can be dissociated. An alternative hypothesis suggests that confidence instead reflects the magnitude of evidence in favor of a decision while being relatively insensitive to the evidence opposing the decision. We considered how this alternative hypothesis might be biologically instantiated by developing a simple neural network model incorporating a known property of sensory neurons: tuned inhibition. The key idea of the model is that the level of inhibition that each accumulator unit receives from units with the opposite tuning preference, i.e. its inhibition ‘tuning’, dictates its contribution to perceptual decisions versus confidence judgments, such that units with higher tuned inhibition (computing relative evidence for different perceptual interpretations) determine perceptual discrimination decisions, and units with lower tuned inhibition (computing absolute evidence) determine confidence. We demonstrate that this biologically plausible model can account for several counterintuitive findings reported in the literature where confidence and decision accuracy dissociate. By comparing model fits, we further demonstrate that a full complement of behavioral data across several previously published experimental results—including accuracy, reaction time, mean confidence, and metacognitive sensitivity—is best accounted for when confidence is computed from units without, rather than units with, tuned inhibition. Finally, we discuss predictions of our results and model for future neurobiological studies. These findings suggest that the brain has developed and implements this alternative, heuristic theory of perceptual confidence computation by relying on the diversity of neural resources available.     

Predicting knee adduction moment response to gait retraining with minimal clinical data

Knee osteoarthritis is a progressive disease mediated by high joint loads. Foot progression angle modifications that reduce the knee adduction moment (KAM), a surrogate of knee loading, have demonstrated efficacy in alleviating pain and improving function. Although changes to the foot progression angle are overall beneficial, KAM reductions are not consistent across patients. Moreover, customized interventions are time-consuming and require instrumentation not commonly available in the clinic. We present a regression model that uses minimal clinical data—a set of six features easily obtained in the clinic—to predict the extent of first peak KAM reduction after toe-in gait retraining. For such a model to generalize, the training data must be large and variable. Given the lack of large public datasets that contain different gaits for the same patient, we generated this dataset synthetically. Insights learned from a ground-truth dataset with both baseline and toe-in gait trials (N = 12) enabled the creation of a large (N = 138) synthetic dataset for training the predictive model. On a test set of data collected by a separate research group (N = 15), the first peak KAM reduction was predicted with a mean absolute error of 0.134% body weight * height (%BW*HT). This error is smaller than the standard deviation of the first peak KAM during baseline walking averaged across test subjects (0.306%BW*HT). This work demonstrates the feasibility of training predictive models with synthetic data and provides clinicians with a new tool to predict the outcome of patient-specific gait retraining without requiring gait lab instrumentation.     

An Image Encryption Algorithm Utilizing Julia Sets and Hilbert Curves

Image encryption is an important and effective technique to protect image security. In this paper, a novel image encryption algorithm combining Julia sets and Hilbert curves is proposed. The algorithm utilizes Julia sets’ parameters to generate a random sequence as the initial keys and gets the final encryption keys by scrambling the initial keys through the Hilbert curve. The final cipher image is obtained by modulo arithmetic and diffuse operation. In this method, it needs only a few parameters for the key generation, which greatly reduces the storage space. Moreover, because of the Julia sets’ properties, such as infiniteness and chaotic characteristics, the keys have high sensitivity even to a tiny perturbation. The experimental results indicate that the algorithm has large key space, good statistical property, high sensitivity for the keys, and effective resistance to the chosen-plaintext attack.     

Insect-Inspired Navigation Algorithm for an Aerial Agent Using Satellite Imagery

Humans have long marveled at the ability of animals to navigate swiftly, accurately, and across long distances. Many mechanisms have been proposed for how animals acquire, store, and retrace learned routes, yet many of these hypotheses appear incongruent with behavioral observations and the animals’ neural constraints. The “Navigation by Scene Familiarity Hypothesis” proposed originally for insect navigation offers an elegantly simple solution for retracing previously experienced routes without the need for complex neural architectures and memory retrieval mechanisms. This hypothesis proposes that an animal can return to a target location by simply moving toward the most familiar scene at any given point. Proof of concept simulations have used computer-generated ant’s-eye views of the world, but here we test the ability of scene familiarity algorithms to navigate training routes across satellite images extracted from Google Maps. We find that Google satellite images are so rich in visual information that familiarity algorithms can be used to retrace even tortuous routes with low-resolution sensors. We discuss the implications of these findings not only for animal navigation but also for the potential development of visual augmentation systems and robot guidance algorithms.     

Traits across trophic levels interact to influence parasitoid establishment in biological control releases

A central goal in ecology is to predict what governs a species’ ability to establish in a new environment. One mechanism driving establishment success is individual species’ traits, but the role of trait combinations among interacting species across different trophic levels is less clear. Deliberate or accidental species additions to existing communities provide opportunities to study larger scale patterns of establishment success. Biological control introductions are especially valuable because they contain data on both the successfully established and unestablished species. Here, we used a recent dataset of importation biological control introductions to explore how life‐history traits of 132 parasitoid species and their herbivorous hosts interact to affect parasitoid establishment. We find that of five parasitoid and herbivore traits investigated, one parasitoid trait—host range—weakly predicts parasitoid establishment; parasitoids with higher levels of phylogenetic specialization have higher establishment success, though the effect is marginal. In addition, parasitoids are more likely to establish when their herbivore host has had a shorter residence time. Interestingly, we do not corroborate earlier findings that gregarious parasitoids and endoparasitoids are more likely to establish. Most importantly, we find that life‐history traits of the parasitoid species and their hosts can interact to influence establishment. Specifically, parasitoids with broader host ranges are more likely to establish when the herbivore they have been released to control is also more of a generalist. These results provide insight into how multiple species’ traits and their interactions, both within and across trophic levels, can influence establishment of species of higher trophic levels.     

Why Do Some People Do “More” to Mitigate Climate Change than Others? Exploring Heterogeneity in Psycho-Social Associations

The urgency of climate change mitigation calls for a profound shift in personal behavior. This paper investigates psycho-social correlates of extra mitigation behavior in response to climate change, while also testing for potential (unobserved) heterogeneity in European citizens'' decision-making. A person''s extra mitigation behavior in response to climate change is conceptualized—and differentiated from common mitigation behavior—as some people''s broader and greater levels of behavioral engagement (compared to others) across specific self-reported mitigation actions and behavioral domains. Regression analyses highlight the importance of environmental psychographics (i.e., attitudes, motivations, and knowledge about climate change) and socio-demographics (especially country-level variables) in understanding extra mitigation behavior. By looking at the data through the lens of segmentation, significant heterogeneity is uncovered in the associations of attitudes and knowledge about climate change—but not in motivational or socio-demographic links—with extra mitigation behavior in response to climate change, across two groups of environmentally active respondents. The study has implications for promoting more ambitious behavioral responses to climate change, both at the individual level and across countries.     

Eyes Wide Shut: Amygdala Mediates Eyes-Closed Effect on Emotional Experience with Music

The perceived emotional value of stimuli and, as a consequence the subjective emotional experience with them, can be affected by context-dependent styles of processing. Therefore, the investigation of the neural correlates of emotional experience requires accounting for such a variable, a matter of an experimental challenge. Closing the eyes affects the style of attending to auditory stimuli by modifying the perceptual relationship with the environment without changing the stimulus itself. In the current study, we used fMRI to characterize the neural mediators of such modification on the experience of emotionality in music. We assumed that closed eyes position will reveal interplay between different levels of neural processing of emotions. More specifically, we focused on the amygdala as a central node of the limbic system and on its co-activation with the Locus Ceruleus (LC) and Ventral Prefrontal Cortex (VPFC); regions involved in processing of, respectively, ‘low’, visceral-, and ‘high’, cognitive-related, values of emotional stimuli. Fifteen healthy subjects listened to negative and neutral music excerpts with eyes closed or open. As expected, behavioral results showed that closing the eyes while listening to emotional music resulted in enhanced rating of emotionality, specifically of negative music. In correspondence, fMRI results showed greater activation in the amygdala when subjects listened to the emotional music with eyes closed relative to eyes open. More so, by using voxel-based correlation and a dynamic causal model analyses we demonstrated that increased amygdala activation to negative music with eyes closed led to increased activations in the LC and VPFC. This finding supports a system-based model of perceived emotionality in which the amygdala has a central role in mediating the effect of context-based processing style by recruiting neural operations involved in both visceral (i.e. ‘low’) and cognitive (i.e. ‘high’) related processes of emotions.     

Hyper-Brain Networks Support Romantic Kissing in Humans

Coordinated social interaction is associated with, and presumably dependent on, oscillatory couplings within and between brains, which, in turn, consist of an interplay across different frequencies. Here, we introduce a method of network construction based on the cross-frequency coupling (CFC) and examine whether coordinated social interaction is associated with CFC within and between brains. Specifically, we compare the electroencephalograms (EEG) of 15 heterosexual couples during romantic kissing to kissing one’s own hand, and to kissing one another while performing silent arithmetic. Using graph-theory methods, we identify theta–alpha hyper-brain networks, with alpha serving a cleaving or pacemaker function. Network strengths were higher and characteristic path lengths shorter when individuals were kissing each other than when they were kissing their own hand. In both partner-oriented kissing conditions, greater strength and shorter path length for 5-Hz oscillation nodes correlated reliably with greater partner-oriented kissing satisfaction. This correlation was especially strong for inter-brain connections in both partner-oriented kissing conditions but not during kissing one’s own hand. Kissing quality assessed after the kissing with silent arithmetic correlated reliably with intra-brain strength of 10-Hz oscillation nodes during both romantic kissing and kissing with silent arithmetic. We conclude that hyper-brain networks based on CFC may capture neural mechanisms that support interpersonally coordinated voluntary action and bonding behavior.     

Out of the blue: understanding abrupt and wayward transitions in thought using probability and predictive processing

Thoughts that appear to come to us ‘out of the blue’ or ‘out of nowhere’ are a familiar aspect of mental experience. Such thoughts tend to elicit feelings of surprise and spontaneity. Although we are beginning to understand the neural processes that underlie the arising of such thoughts, little is known about what accounts for their peculiar phenomenology. Here, we focus on one central aspect of this phenomenology—the experience of surprise at their occurrence, as it relates to internal probabilistic predictions regarding mental states. We introduce a distinction between two phenomenologically different types of transitions in thought content: (i) abrupt transitions, which occur at surprising times but lead to unsurprising thought content, and (ii) wayward transitions, which occur at surprising times and also lead to surprising thought content. We examine these two types of transitions using a novel approach that combines probabilistic and predictive processing concepts and principles. We employ two different probability metrics—transition and occurrence probability—to characterize and differentiate between abrupt and wayward transitions. We close by discussing some potentially beneficial ways in which these two kinds of transitions in thought content may contribute to mental function, and how they may be implemented at the neural level.This article is part of the theme issue ‘Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation’.     

Backtracking behaviour in lost ants: an additional strategy in their navigational toolkit

Ants use multiple sources of information to navigate, but do not integrate all this information into a unified representation of the world. Rather, the available information appears to serve three distinct main navigational systems: path integration, systematic search and the use of learnt information—mainly via vision. Here, we report on an additional behaviour that suggests a supplemental system in the ant''s navigational toolkit: ‘backtracking’. Homing ants, having almost reached their nest but, suddenly displaced to unfamiliar areas, did not show the characteristic undirected headings of systematic searches. Instead, these ants backtracked in the compass direction opposite to the path that they had just travelled. The ecological function of this behaviour is clear as we show it increases the chances of returning to familiar terrain. Importantly, the mechanistic implications of this behaviour stress an extra level of cognitive complexity in ant navigation. Our results imply: (i) the presence of a type of ‘memory of the current trip’ allowing lost ants to take into account the familiar view recently experienced, and (ii) direct sharing of information across different navigational systems. We propose a revised architecture of the ant''s navigational toolkit illustrating how the different systems may interact to produce adaptive behaviours.