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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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Structured flexibility in recurrent neural networks via neuromodulation

The goal of theoretical neuroscience is to develop models that help us better understand biological intelligence. Such models range broadly in complexity and biological detail. For example, task-optimized recurrent neural networks (RNNs) have generated hypotheses about how the brain may perform various computations, but these models typically assume a fixed weight matrix representing the synaptic connectivity between neurons. From decades of neuroscience research, we know that synaptic weights are constantly changing, controlled in part by chemicals such as neuromodulators. In this work we explore the computational implications of synaptic gain scaling, a form of neuromodulation, using task-optimized low-rank RNNs. In our neuromodulated RNN (NM-RNN) model, a neuromodulatory subnetwork outputs a low-dimensional neuromodulatory signal that dynamically scales the low-rank recurrent weights of an output-generating RNN. In empirical experiments, we find that the structured flexibility in the NM-RNN allows it to both train and generalize with a higher degree of accuracy than low-rank RNNs on a set of canonical tasks. Additionally, via theoretical analyses we show how neuromodulatory gain scaling endows networks with gating mechanisms commonly found in artificial RNNs. We end by analyzing the low-rank dynamics of trai ned NM-RNNs, to show how task computations are distributed.

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MIND WANDERING DURING IMPLICIT LEARNING IS ASSOCIATED WITH INCREASED PERIODIC EEG ACTIVITY AND IMPROVED EXTRACTION OF HIDDEN PROBABILISTIC PATTERNS

Mind wandering, occupying 30-50% of our waking time, remains an enigmatic phenomenon in cognitive neuroscience. Predominantly viewed negatively, mind wandering is often associated with detrimental impacts on attention-demanding (model-based) tasks in both natural settings and laboratory conditions. Mind wandering however, might not be detrimental for all cognitive domains. We proposed that mind wandering may facilitate model-free processes, such as probabilistic learning, which relies on the automatic acquisition of statistical regularities with minimal attentional demands. We administered a well-established implicit probabilistic learning task combined with mind wandering thought probes in healthy adults (N = 37, 30 females). To explore the neural correlates of mind wandering and probabilistic learning, participants were fitted with high-density electroencephalography. Our findings indicate that probabilistic learning was not only immune to periods of mind wandering, but was positively associated with it. Spontaneous, as opposed to deliberate mind wandering, was particularly beneficial for extracting the probabilistic patterns hidden in the visual stream. Additionally, cortical oscillatory activity in the low-frequency (slow and delta) range, indicative of covert sleep-like states, was associated with both mind wandering and improved probabilistic learning, particularly in the early stages of the task. Given the importance of probabilistic implicit learning in predictive processing, our findings provide novel insights into the potential cognitive benefits of task-unrelated thoughts in addition to shedding light on its neural mechanisms. This surprising benefit challenges the predominant view of mind wandering as solely detrimental and highlights its complex role in human cognition, especially in memory consolidation. Statement of significanceMind wandering poses an unresolved puzzle for cognitive neuroscience: it is associated with poor performance in various cognitive domains, yet humans spend 30-50% of their waking time mind wandering. We proposed that mind wandering may be beneficial for less attention-demanding cognitive processes requiring automatic, habitual learning. We assessed an implicit probabilistic learning task measuring the ability to extract (without awareness) hidden regularities from the information stream. Participants showed superior performance in probabilistic learning during periods of mind wandering, especially when such task-unrelated thoughts occurred spontaneously without intention. Moreover, mind wandering and probabilistic learning were both associated with slow frequency neural activity, suggesting that mind wandering may reflect a transient, offline state facilitating rapid learning and memory consolidation.

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Spatial transcriptomic data reveals pure cell types via the mosaic hypothesis

Neurons display remarkable diversity in their anatomical, molecular, and physiological properties. Although observed stereotypy in subsets of neurons is a pillar of neuroscience, clustering in high-dimensional feature spaces, such as those defined by single-cell RNA-seq data, is often inconclusive, with cells seemingly occupying continuous, rather than discrete, regions. In the retina, a layered structure, neurons of the same discrete type avoid spatial proximity with each other. While this principle, which is independent of clustering in feature space, has been a gold standard for retinal cell types, its applicability to the cortex has been only sparsely explored. Here, we provide evidence for such a mosaic hypothesis by developing a statistical point process analysis framework for spatial transcriptomic data. We demonstrate spatial avoidance across many excitatory and inhibitory neuronal types. Spatial avoidance disappears when cell types are merged, potentially offering a gold standard metric for evaluating the purity of putative cell types. Significance statementWhile morphologically or molecularly-defined cell types and their taxonomy are a pillar of modern neuroscience, the extent to which their discrete treatment reflects biology is far from settled. A functional hypothesis concerning cortical neuronal cell types with roots in retina research suggests an anatomical test for the existence and identification of pure, discrete cell types. We describe evidence for this decades-old hypothesis in the mouse neocortex and detail the associated computational methodology based on spatial point processes.

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A Biologically Inspired Attention Model for Neural Signal Analysis

Understanding how the brain represents sensory information and triggers behavioural responses is a fundamental goal in neuroscience. Recent advances in neuronal recording techniques aim to progress towards this milestone, yet the resulting high-dimensional responses are challenging to interpret and link to relevant variables. Although existing machine learning models propose to do so, they often sacrifice interpretability for predictive power, effectively operating as black boxes. In this work, we introduce SPARKS, a biologically inspired model capable of high decoding accuracy and interpretable discovery within a single framework. SPARKS adapts the self-attention mechanism of large language models to extract information from the timing of single spikes and the sequence in which neurons fire using Hebbian learning. Trained with a criterion inspired by predictive coding to enforce temporal coherence, our model produces low-dimensional latent embeddings that are robust across sessions and animals. By directly capturing the underlying data distribution through a generative encoding-decoding framework, SPARKS exhibits state-of-the-art predictive capabilities across diverse electrophysiology and calcium imaging datasets from the motor, visual and entorhinal cortices. Crucially, the Hebbian coefficients learned by the model are interpretable, allowing us to infer the effective connectivity and recover the known functional hierarchy of the mouse visual cortex. Overall, SPARKS unifies representation learning, high-performance decoding and model interpretability in a single framework by bridging neuroscience and AI, providing a powerful and versatile tool for dissecting neural computations and marking a step towards the next generation of biologically inspired intelligent systems.

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Fast implicit and slow explicit learning of temporal context in cortico-cerebellar loops

One is seldom aware of the anticipatory and preemptive feats that the eyeblink systems achieves in daily life but it frequently protects the eye from projectiles gone awry and insects on apparent collision courses. This poor awareness is why predictive eyeblinks are considered a form of implicit learning. In motor neuroscience, implicit learning is considered to be slow and, eyeblink conditioning, in particular, is believed to be a rigid and inflexible cerebellar-dependent behavior. In cognitive neuroscience, however, implicit and automatic processes are thought to be rapidly acquired. Here we show that the eyeblink system is, in fact, capable of remarkable cognitive flexibility and can learn on more rapid timescales than previously expected. In a task where we yoked contextual learning of predictive eyeblinks and manual responses in humans, well-timed eyeblink responses flexibly adjusted to external context on each trial. The temporal precision of the predictive eyeblinks exceeded that of manual response times. Learning of the well-timed eyeblink responses was also more rapid than that for the manual response times. This pattern persevered with the use of a cognitive strategy, which seemed to accelerate both types of learning. These results suggest that behaviors associated with the cerebellar cortex that were previously believed to be inflexible and largely implicit, can demonstrate rapid and precise context-dependent temporal control.

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Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

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Human deep sleep facilitates faster cerebrospinal fluid dynamics linked to brain oscillations for sleep homeostasis and memory

How sleep maintains our healthy brain function has remained one of the biggest mysteries in neuroscience, medical settings, and daily lives. While cerebrospinal fluid (CSF) during sleep have been implicated in metabolic waste reduction in animals, how CSF dynamics are driven in the healthy human brain during deep sleep remains elusive. A myriad of research has shown that crucial cognitive processing manifests in slow wave and rapid-eye movement (REM) sleep, suggesting that a key to maintaining brain functions lies in deep sleep. By leveraging a simultaneous sparse-fMRI and polysomnography method, we demonstrate that deep sleep-specific faster CSF dynamics are associated with spontaneous brain oscillations in healthy young human participants. Slow waves and sleep spindles during slow-wave sleep and rapid eye movements and sawtooth waves during rapid eye movement (REM) sleep are tightly linked to low-amplitude faster CSF fluctuations. In contrast, slow waves during light sleep and arousals produced large but slower CSF signal changes. Furthermore, CSF signals are significantly faster in frequency during deep than light sleep. These brain oscillations during light and deep sleep recruited essentially different brain networks, with deep sleep involving memory and homeostatic circuits. Thus, human deep sleep has a unique way of enabling faster CSF dynamics that are distinctive from arousal mechanisms. Significance StatementSleep is indispensable to our life, but its functions remain a significant mystery in the field of neuroscience. One of the most enigmatic issues in sleep is whether and how sleep regulates the CSF. The present study demonstrates deep sleep-specific faster CSF dynamics time locked to sleep brain oscillations in healthy young human participants. Slow waves and sleep spindles during slow-wave sleep and rapid eye movements and sawtooth waves during REM sleep are tightly linked to CSF fluctuations, contributing to faster CSF signals. Our results consistently demonstrate that human deep sleep has a unique way of enabling faster CSF dynamics that are distinctive from arousal mechanisms.

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Addressing inconsistency in functional neuroimaging: A replicable data-driven multi-scale functional atlas for canonical brain networks

The advent of multiple neuroimaging methodologies has greatly aided in the conceptualization of large-scale functional brain networks in the field of cognitive neuroscience. However, there is inconsistency across studies in both nomenclature and the functional entities being described. There is a need for a unifying framework that standardizes terminology across studies while also bringing analyses and results into the same reference space. Here we present a whole-brain atlas of canonical functional brain networks derived from more than 100,000 resting-state fMRI datasets. These data-driven functional networks are highly replicable across datasets and capture information from multiple spatial scales. We have organized, labeled, and described the networks with terms familiar to the fields of cognitive and affective neuroscience in order to optimize their utility in future neuroimaging analyses and enhance the accessibility of new findings. The benefits of this atlas are not limited to future template-based or reference-guided analyses, but also extend to other data-driven neuroimaging approaches across modalities, such as those using blind independent component analysis (ICA). Future studies utilizing this atlas will contribute to greater harmonization and standardization in functional neuroimaging research.

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Brain plasticity for visual words: Elementary school teachers can drive changes in weeks that rival those formed over years

This study aims to investigate the impact of vocabulary acquisition through short-term classroom learning and its relation to broader forms of vocabulary learning through long-term exposure in daily life. Through a two week of "learning sprint" in collaboration with a local elementary school and EEG-Steady State Visual Evoked Potentials (EEG-SSVEP) paradigm, we assessed new vocabulary learning in first and second graders within their pedagogical environment. We then compared the results with the word frequency effect, a well-established phenonmenon that reflects long-term vocabulary learning. After two weeks of classroom instruction, newly acquired words elicited neural responses similar to those of high-frequency words, with the effect significantly correlated with childrens phonological decoding skills. Additionally, we successfully replicated the word frequency effect using the SSVEP paradigm for the first time. These findings highlight the potential of the "learning sprint" model for conducting neuroscience research in authentic educational settings, thereby fostering a stronger connection between education and neuroscience.

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Vocal Call Locator Benchmark (VCL) for localizing rodent vocalizations from multi-channel audio

Understanding the behavioral and neural dynamics of social interactions is a goal of contemporary neuroscience. Many machine learning methods have emerged in recent years to make sense of complex video and neurophysiological data that result from these experiments. Less focus has been placed on understanding how animals process acoustic information, including social vocalizations. A critical step to bridge this gap is determining the senders and receivers of acoustic information in social interactions. While sound source localization (SSL) is a classic problem in signal processing, existing approaches are limited in their ability to localize animal-generated sounds in standard laboratory environments. Advances in deep learning methods for SSL are likely to help address these limitations, however there are currently no publicly available models, datasets, or benchmarks to systematically evaluate SSL algorithms in the domain of bioacoustics. Here, we present the VCL Benchmark: the first large-scale dataset for benchmarking SSL algorithms in rodents. We acquired synchronized video and multi-channel audio recordings of 767,295 sounds with annotated ground truth sources across 9 conditions. The dataset provides benchmarks which evaluate SSL performance on real data, simulated acoustic data, and a mixture of real and simulated data. We intend for this benchmark to facilitate knowledge transfer between the neuroscience and acoustic machine learning communities, which have had limited overlap.

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How neural network structure alters the brain's self-organized criticality

The brain criticality hypothesis has been a central research topic in theoretical neuroscience for two decades. This hypothesis suggests that the brain operates near the critical point at the boundary between order and disorder, where it acquires its information-processing capabilities. The mechanism that maintains this critical state has been proposed as a feedback system known as self-organized criticality (SOC); brain parameters, such as synaptic plasticity, are regulated internally without external adjustment. Therefore, clarifying how SOC occurs can help us to understand the mechanisms that maintain brain function and cause brain disorders. From the standpoint of neural network structures, the topology of neural circuits also plays a crucial role in information processing, with healthy neural networks exhibiting small-world, scale-free, and modular characteristics. However, how these network structures affect SOC remains poorly understood. In this study, we numerically investigated the possibility that the structure of neural networks contributes to the brains critical state and dysfunction using a mathematical model. Our results reveal that the time scales at which synaptic plasticity operates to achieve a critical state differ depending on the network structure. Additionally, we observed Dragon king phenomena associated with abnormal neural activity, depending on the network structure and synaptic plasticity time scales. Notably, Dragon king was observed over a wide range of synaptic plasticity time scales in scale-free networks with high-degree hub nodes. This study emphasizes the importance of neural network topology in neuroscience from the perspective of SOC.

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WTools: a MATLAB-based toolbox for time-frequency analysis

Electroencephalography (EEG) is an established method for investigating neurocognitive functions during human development. In cognitive neuroscience, time-frequency analysis of the EEG is a widely used analytical approach. This paper introduces WTools, a new MATLAB-based toolbox capable of performing time-frequency analysis of EEG signals using complex wavelet transformation. WTools features an intuitive GUI that guides users through the analysis steps, focusing on essential parameters. Being free and open-source, it can be integrated and expanded with new features, making it a handy tool that is growing its popularity in developmental cognitive neuroscience. Here, we provide a detailed description of the WTools algorithm for wavelet transformation and we compare it with state-of-the-art methods implemented in EEGLAB. Alongside the official tool release, we also offer a comprehensive illustrated tutorial to enhance accessibility and promote the transparent and reproducible usage of WTools by the scientific community. HighlightsO_LIWTools is a new MATLAB-based toolbox for time-frequency analysis of the EEG signal C_LIO_LIIt uses wavelet transformation and the algorithm is fully described C_LIO_LIIt is designed to be very user friendly through its simple GUI C_LIO_LIIt is open source and flexible as the code is freely available C_LIO_LIWe provide a step-by-step tutorial and an example dataset to learn the toolbox C_LI

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Aperiodic exponent of brain field potentials is dependent on the frequency range it is estimated

The aperiodic component of brain field potentials, like EEG, LFP and intracortical recordings, has shown to be a valuable tool in basic neuroscience and in clinical applications. Aperiodic activity is modeled as a power law of the power spectral density, with the aperiodic exponent as the key parameter. Part of the interest in this parameter lies in its proposed role as a marker of the balance between excitatory and inhibitory cortical activity. In theory, a perfect power law would imply that the same behaviour exists across all frequencies, however recent evidence has suggested that low and high frequency ranges could present different aperiodic exponents. To elucidate this, we systematically evaluated the relation between frequency range and aperiodic parameters using human resting-state intracortical recordings from 62 patients. We employed two distinct estimation methods, Specparam and IRASA. We found that aperiodic parameters were indeed dependent on frequency range. Specifically, we found that low frequency ranges displayed, on average, lower aperiodic exponents (flatter power spectral density) than high frequency ranges. This behaviour was consistent for Specparam and IRASA estimations in all frequency ranges compatible with EEG. Given that there is currently no consensus for a single frequency range to be used in either clinical or basic neuroscience, our results show that care should be taken when comparing aperiodic exponents derived from different frequency ranges. We believe our results also encourage further research into the possible roles that aperiodic exponents estimated from different frequency ranges could have in reflecting distinct aspects of cortical systems.

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Using deep generative models for simultaneous representational and predictive modeling of brain and behavior: A graded supervised-to-unsupervised modeling framework.

This paper uses a generative neural network architecture combining unsupervised (generative) and supervised (discriminative) models with a model comparison strategy to evaluate assumptions about the mappings between brain states and behavior. Most modeling in cognitive neuroscience publications assume a one-to-one brain-behavior relationship that is linear, but never test these assumptions or the consequences of violating them. We systematically varied these assumptions using simulations of four ground-truth brain-behavior mappings that involve progressively more complex relationships, ranging from one-to-one linear mappings to many-to-one nonlinear mappings. We then applied our Variational AutoEncoder-Classifier framework to the simulations to show how it accurately captured diverse brain-behavior mappings,provided evidence regarding which assumptions are supported by the data, and illustrated the problems that arise when assumptions are violated. This integrated approach offers a reliable foundation for cognitive neuroscience to effectively model complex neural and behavioral processes, allowing more justified conclusions about the nature of brain-behavior mappings.

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Virtual Brain Inference (VBI): A flexible and integrative toolkit for efficient probabilistic inference on virtual brain models

Network neuroscience has proven essential for understanding the principles and mechanisms underlying complex brain (dys)function and cognition. In this context, whole-brain network modeling-also known as virtual brain modeling-combines computational models of brain dynamics (placed at each network node) with individual brain imaging data (to coordinate and connect the nodes), advancing our understanding of the complex dynamics of the brain and its neurobiological underpinnings. However, there remains a critical need for automated model inversion tools to estimate control (bifurcation) parameters at large scales associated with neuroimaging modalities, given their varying spatio-temporal resolutions. This study aims to address this gap by introducing a flexible and integrative toolkit for efficient Bayesian inference on virtual brain models, called Virtual Brain Inference (VBI). This open-source toolkit provides fast simulations, taxonomy of feature extraction, efficient data storage and loading, and probabilistic machine learning algorithms, enabling biophysically interpretable inference from non-invasive and invasive recordings. Through in-silico testing, we demonstrate the accuracy and reliability of inference for commonly used whole-brain network models and their associated neuroimaging data. VBI shows potential to improve hypothesis evaluation in network neuroscience through uncertainty quantification, and contribute to advances in precision medicine by enhancing the predictive power of virtual brain models.

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3D markerless tracking of speech movements with submillimeter accuracy

Speech movements are highly complex and require precise tuning of both spatial and timing of oral articulators to support intelligible communication. These properties also make measurement of speech movements challenging, often requiring extensive physical sensors placed around the mouth and face that are not easily tolerated by certain populations such as young children. Recent progress in machine learning-based markerless facial landmark tracking technology demonstrated its potential to provide lip tracking without the need for physical sensors, but whether such technology can provide submillimeter precision and accuracy in 3D remains unknown. Moreover, it is also unclear whether such technology can be applied to track speech movements in young children. Here, we developed a novel approach that integrates Shape Preserving Facial Landmarks with Graph Attention Networks (SPIGA), a facial landmark detector, and CoTracker, a transformer-based neural network model that jointly tracks dense points across a video sequence. We further examined and validated this novel approach by assessing its tracking precision and accuracy. The findings revealed that our approach that integrates SPIGA and CoTracker was more precise ({approx} 0.15 mm in standard deviation) than SPIGA alone ({approx} 0.35 mm). In addition, its 3D tracking performance was comparable to electromagnetic articulography ({approx} 0.29 mm RMSE against simultaneously recorded articulograph data). Importantly, the approach performed similarly well across adults and young children (i.e., 3- and 4-year-olds). Because our framework is built upon open-source pretrained models that are fully trained, it promotes accessibility and open science while saving computing resources. Furthermore, given that this framework combines a landmark detection model (SPIGA) with a tracker model (CoTracker) to improve precision/accuracy, our novel approach serves as a proof-of-concept for enhancing the performance of a wide variety of commonly used markerless tracking applications in biology and neuroscience. Author summaryIn this work, we examined whether machine learning based markerless tracking is feasible for tracking 3D lip movements in adults and young children. We developed a novel approach that integrates a landmark detection model (SPIGA) with a tracker model (CoTracker). Our combined CoTracker-based approach demonstrated submillimeter precision and accuracy desired for speech kinematic recording. In addition, our approach does not involve training and validation for each population (e.g., young children vs. adults), saving time and computing resources. We foresee that the proposed general framework of fusing a landmark detection model with a tracker model can be generalized for a wide variety of tracking applications in biology and neuroscience that require high precision and accuracy, including studying cell behaviors, animal motions, and other types of human movements.

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The neural basis of creative thought: An activation likelihood estimation meta-analysis involving over 17,000 participants

Humans can create impressive art, make major scientific breakthroughs, and generate creative solutions that solve everyday life problems. But how are these creative activities supported by the brain? This question is of great scientific interest but remains unanswered. New hypotheses, grounded in converging evidence from cognitive neuroscience, are needed to guide breakthroughs in understanding the neural basis of creative thought. It has long been suggested that creativity is a distinct mental function. However, converging clinical-cognitive neuroscience evidence is starting to suggest that creative thought is not functionally distinct but, instead, might arise from general purpose cognitive mechanisms supporting semantic cognition, controlled episodic memory retrieval, and executive mechanisms (i.e., Cognitive Cornerstones Hypothesis; Chan et al., 2023). Results from this large-scale activation likelihood estimation (ALE) meta-analysis, based on 787 experiments with 10,357 foci from 17,228 healthy adult participants, showed that the brain regions implicated in creativity tasks heavily overlap with the brain regions implicated in the cognitive cornerstones of creative thought (i.e., pre-existing knowledge and executive mechanisms). These striking results suggest that innovative insights will arise from considering the roles of these fundamental cognitive functions and their interactions in supporting creative thought.

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Rapid modulation of choice behavior by ultrasound on the human frontal eye fields

A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation (TUS) offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise TUS protocol targeting the frontal eye fields (FEFs) -- a well-characterized circuit critical for saccadic eye movements. We demonstrate that TUS induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish TUS as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted TUS applications in neuroscience and clinical settings. HighlightsO_LIFocused ultrasound modulates saccades with high spatial and temporal precision C_LIO_LIInhibitory circuits in the frontal eye fields shape choice computations C_LIO_LIGABA levels predict individual variability in ultrasound-induced behavioral changes C_LIO_LIUltrasound can be used to probe fast neural dynamics and individual differences C_LI

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