Open Question In Neuroscience Research Articles

Dynamic changes in subplate and cortical plate microstructure at the onset of cortical folding in vivo.

Cortical gyrification takes place predominantly during the second to third trimester, alongside other fundamental developmental processes, such as the development of white matter connections, lamination of the cortex and formation of neural circuits. The mechanistic biology that drives the formation cortical folding patterns remains an open question in neuroscience. In our previous work, we modelled the in utero diffusion signal to quantify the maturation of microstructure in transient fetal compartments, identifying patterns of change in diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester. In this work, we apply the same modelling approach to explore whether microstructural maturation of these compartments is correlated with the process of gyrification. We quantify the relationship between sulcal depth and tissue anisotropy within the cortical plate (CP) and underlying subplate (SP), key transient fetal compartments often implicated in mechanistic hypotheses about the onset of gyrification. Using in utero high angular resolution multi-shell diffusion-weighted imaging (HARDI) from the Developing Human Connectome Project (dHCP), our analysis reveals that the anisotropic, tissue component of the diffusion signal in the SP and CP decreases immediately prior to the formation of sulcal pits in the fetal brain. By back-projecting a map of folded brain regions onto the unfolded brain, we find evidence for cytoarchitectural differences between gyral and sulcal areas in the late second trimester, suggesting that regional variation in the microstructure of transient fetal compartments precedes, and thus may have a mechanistic function, in the onset of cortical folding in the developing human brain.

Neuromodulatory control of complex adaptive dynamics in the brain.

How is the massive dimensionality and complexity of the microscopic constituents of the nervous system brought under sufficiently tight control so as to coordinate adaptive behaviour? A powerful means for striking this balance is to poise neurons close to the critical point of a phase transition, at which a small change in neuronal excitability can manifest a nonlinear augmentation in neuronal activity. How the brain could mediate this critical transition is a key open question in neuroscience. Here, I propose that the different arms of the ascending arousal system provide the brain with a diverse set of heterogeneous control parameters that can be used to modulate the excitability and receptivity of target neurons-in other words, to act as control parameters for mediating critical neuronal order. Through a series of worked examples, I demonstrate how the neuromodulatory arousal system can interact with the inherent topological complexity of neuronal subsystems in the brain to mediate complex adaptive behaviour.

Combining Cortical Voltage Imaging and Hippocampal Electrophysiology for Investigating Global, Multi-Timescale Activity Interactions in the Brain.

A new generation of optogenetic tools for analyzing neural activity has been contributing to the elucidation of classical open questions in neuroscience. Specifically, voltage imaging technologies using enhanced genetically encoded voltage indicators have been increasingly used to observe the dynamics of large circuits at the mesoscale. Here, we describe how to combine cortical wide-field voltage imaging with hippocampal electrophysiology in awake, behaving mice. Furthermore, we highlight how this method can be useful for different possible investigations, using the characterization of hippocampal–neocortical interactions as a case study.

Central nervous system autopsy - a neuropathological procedure based on multidisciplinary pathoclinical cooperation.

Neuropathological brain and spinal cord post mortem examination is a distinct procedure that still plays an important role in modern medicine. In front of increasing amounts of clinical and genetic data, together with important developments in the field of neuroimaging, the Polish Association of Neuropathologists have updated their recommendations regarding central nervous system (CNS) examination. These guidelines are aimed at neuropathologists, pathologists and clinicians. Presentation of the outlined recommendations as their goal is to improve the quality, informativity, and cost effectiveness of CNS post mortem examinations. A comprehensive study of the literature was conducted to provide a clinical background of neuropathological autopsy. There are numerous open questions in neuroscience, and new strategies are required to foster research in CNS diseases. These include the challenge of organizing brain banks tasked with managing and protecting detailed multidisciplinary information about their resources. Complex neuropathological analyses of post mortem series are also important to assess the effectiveness of diagnostics and therapy, identify environmental impact on the development of neurological disorders, and improve public health policy. The recommendations outline the need for collaboration between multiple specialists to establish the proper diagnosis and to broaden knowledge of neurological disorders.

Radical pairs may play a role in microtubule reorganization

The exact mechanism behind general anesthesia remains an open question in neuroscience. It has been proposed that anesthetics selectively prevent consciousness and memory via acting on microtubules (MTs). It is known that the magnetic field modulates MT organization. A recent study shows that a radical pair model can explain the isotope effect in xenon-induced anesthesia and predicts magnetic field effects on anesthetic potency. Further, reactive oxygen species are also implicated in MT stability and anesthesia. Based on a simple radical pair mechanism model and a simple mathematical model of MT organization, we show that magnetic fields can modulate spin dynamics of naturally occurring radical pairs in MT. We propose that the spin dynamics influence a rate in the reaction cycle, which translates into a change in the MT density. We can reproduce magnetic field effects on the MT concentration that have been observed. Our model also predicts additional effects at slightly higher fields. Our model further predicts that the effect of zinc on the MT density exhibits isotopic dependence. The findings of this work make a connection between microtubule-based and radical pair-based quantum theories of consciousness.

Classification based on dynamic mode decomposition applied to brain recognition of context

Local Field Potentials (LFPs) are easy to access electrical signals of the brain that represent the summation in the extracellular space, of currents originated within the neurons. As such, LFPs could contain information about ongoing computations in neuronal circuits and could potentially be used to design brain machine interface algorithms. However how brain computations could be decoded from LFPs is not clear. Within this context, a methodology for signal classification is proposed in this study, particularly based on the Dynamic Mode Decomposition method, in conjunction with binary clustering routines based on supervised learning. Note that, although the classification methodology is presented here in the context of a biological problem, it can be applied to a broad range of applications. Then, as a case-study, the proposed method is validated with the classification of LFP-based brain cognitive states. All the analysis, signals, and results shown in this study consider real data measured in the hippocampus, in rats performing exploration tasks. Consequently, it is shown that, using the measured LFP, the method infers which context was the animal exploring. Thus, evidence on the spatial codification in LFP signals is consequently provided, which still is an open question in neuroscience.

Episodic memory governs choices: An RNN-based reinforcement learning model for decision-making task

Typical methods to study cognitive function are to record the electrical activities of animal neurons during the training of animals performing behavioral tasks. A key problem is that they fail to record all the relevant neurons in the animal brain. To alleviate this problem, we develop an RNN-based Actor–Critic framework, which is trained through reinforcement learning (RL) to solve two tasks analogous to the monkeys’ decision-making tasks. The trained model is capable of reproducing some features of neural activities recorded from animal brain, or some behavior properties exhibited in animal experiments, suggesting that it can serve as a computational platform to explore other cognitive functions. Furthermore, we conduct behavioral experiments on our framework, trying to explore an open question in neuroscience: which episodic memory in the hippocampus should be selected to ultimately govern future decisions. We find that the retrieval of salient events sampled from episodic memories can effectively shorten deliberation time than common events in the decision-making process. The results indicate that salient events stored in the hippocampus could be prioritized to propagate reward information, and thus allow decision-makers to learn a strategy faster.

The small scale functional topology of movement control: Hierarchical organization of local activity anticipates movement generation in the premotor cortex of primates

How neurons coordinate their collective activity for behavioural control is an open question in neuroscience. Several studies have progressively proven, on various scales, that the patterns of neural synchronization change accordingly with behavioural events. However, the topological features of the neural dynamics that underlie task-based cognitive decisions on the small scale level are not understood. We analysed the multiunit activity (MUA) from a multielectrode (96 channels) array of the dorsal premotor cortex (PMd) in rhesus monkeys during a countermanding reaching task. Within the framework of graph theory, we found that in the local PMd network motor execution is preceded by the emergence of hubs of anti-correlation that are organized in a hierarchical manner. Conversely, this organization is absent when monkeys correctly inhibit programmed movements. Thus, we interpret the presence of hubs as reflecting the readiness of the motor plan and the irrevocable signature of the onset of the incoming movement.

Subcortical neural correlates of behavior in the auditory system

One of the biggest open questions in neuroscience is the relationship between neuronal activity and behavior. Little is known in the auditory system about the nature of the relationship between stimulus encoding and perception. To shed light on this topic, we recorded responses of single neurons in the central nucleus of the inferior colliculus (CNIC) and cochlear nucleus (CN) of macaques that were trained to detect tones or vowels during behavioral performance. Using signal detection theoretic methods, we determined that neurometric tone and vowel detection thresholds based on rate measures in CNIC matched behavioral thresholds, while thresholds of CN neurons were higher than behavior. Additionally, the response magnitudes of a majority of the CNIC neurons varied significantly depending on the behavioral accuracy, compared to a much smaller proportion of CN neurons. Analysis of temporal patterns of response (e.g., phase locking) suggests that neurometric thresholds of all CN and most CNIC neurons matched behavioral thresholds during vowel detection. Additionally, every CNIC and CN neuron showed significant response pattern differences based on behavioral accuracy. These results suggest that behaviorally relevant coding early in the pathway is temporal in nature and is transformed to more rate based measures at higher levels of processing.One of the biggest open questions in neuroscience is the relationship between neuronal activity and behavior. Little is known in the auditory system about the nature of the relationship between stimulus encoding and perception. To shed light on this topic, we recorded responses of single neurons in the central nucleus of the inferior colliculus (CNIC) and cochlear nucleus (CN) of macaques that were trained to detect tones or vowels during behavioral performance. Using signal detection theoretic methods, we determined that neurometric tone and vowel detection thresholds based on rate measures in CNIC matched behavioral thresholds, while thresholds of CN neurons were higher than behavior. Additionally, the response magnitudes of a majority of the CNIC neurons varied significantly depending on the behavioral accuracy, compared to a much smaller proportion of CN neurons. Analysis of temporal patterns of response (e.g., phase locking) suggests that neurometric thresholds of all CN and most CNIC neurons matched...

Automatic decoding of input sinusoidal signal in a neuron model: Improved SNR spectrum by low-pass homomorphic filtering

The principles on how neurons encode and process information from low-level stimuli are still open questions in neuroscience. Neuron models represent useful tools to answer this question but a sensitive method is needed to decode the input information embedded in the neuron spike sequence. In this work, we developed an automatic decoding procedure based on the SNR spectrum improved by low-pass homomorphic filtering. The procedure was applied to a stochastic Hodgkin Huxley neuron model forced by a low-level sinusoidal signal in the range 50 Hz–300 Hz. It exhibited very high performance, in terms of sensitivity and precision, in automatically decoding the input information even when using a relatively small number of model runs (≈ 200). This could provide a fast and valid procedure to understand the encoding mechanisms of low-level sinusoidal stimuli used by different types of neurons.

Visual Space Constructed by Saccade Motor Maps.

How visual space is represented in the brain is an open question in neuroscience. Embodiment theories propose that spatial perception is structured by neural motor maps. Especially, maps which code the targets for saccadic eye movements contain a precise representation of external space. In this review article, we examine how modifications in saccade maps are accompanied by changes in visual space perception. Saccade adaptation, a method which systematically modifies saccade amplitudes, alters the localization of visual objects in space. We illustrate how information about saccade amplitudes is transferred from the cerebellum (CB) to the frontal eye field (FEF). We argue that changes in visual localization after adaptation of saccade maps provide evidence for a shared representation of visual and motor space.

Modularity for Motor Control and Motor Learning.

How the central nervous system (CNS) overcomes the complexity of multi-joint and multi-muscle control and how it acquires or adapts motor skills are fundamental and open questions in neuroscience. A modular architecture may simplify control by embedding features of both the dynamic behavior of the musculoskeletal system and of the task into a small number of modules and by directly mapping task goals into module combination parameters. Several studies of the electromyographic (EMG) activity recorded from many muscles during the performance of different tasks have shown that motor commands are generated by the combination of a small number of muscle synergies, coordinated recruitment of groups of muscles with specific amplitude balances or activation waveforms, thus supporting a modular organization of motor control. Modularity may also help understanding motor learning. In a modular architecture, acquisition of a new motor skill or adaptation of an existing skill after a perturbation may occur at the level of modules or at the level of module combinations. As learning or adapting an existing skill through recombination of modules is likely faster than learning or adapting a skill by acquiring new modules, compatibility with the modules predicts learning difficulty. A recent study in which human subjects used myoelectric control to move a mass in a virtual environment has tested this prediction. By altering the mapping between recorded muscle activity and simulated force applied on the mass, as in a complex surgical rearrangement of the tendons, it has been possible to show that it is easier to adapt to a perturbation that is compatible with the muscle synergies used to generate hand force than to a similar but incompatible perturbation. This result provides direct support for a modular organization of motor control and motor learning.

Task-Driven Activity Reduces the Cortical Activity Space of the Brain: Experiment and Whole-Brain Modeling.

How a stimulus or a task alters the spontaneous dynamics of the brain remains a fundamental open question in neuroscience. One of the most robust hallmarks of task/stimulus-driven brain dynamics is the decrease of variability with respect to the spontaneous level, an effect seen across multiple experimental conditions and in brain signals observed at different spatiotemporal scales. Recently, it was observed that the trial-to-trial variability and temporal variance of functional magnetic resonance imaging (fMRI) signals decrease in the task-driven activity. Here we examined the dynamics of a large-scale model of the human cortex to provide a mechanistic understanding of these observations. The model allows computing the statistics of synaptic activity in the spontaneous condition and in putative tasks determined by external inputs to a given subset of brain regions. We demonstrated that external inputs decrease the variance, increase the covariances, and decrease the autocovariance of synaptic activity as a consequence of single node and large-scale network dynamics. Altogether, these changes in network statistics imply a reduction of entropy, meaning that the spontaneous synaptic activity outlines a larger multidimensional activity space than does the task-driven activity. We tested this model’s prediction on fMRI signals from healthy humans acquired during rest and task conditions and found a significant decrease of entropy in the stimulus-driven activity. Altogether, our study proposes a mechanism for increasing the information capacity of brain networks by enlarging the volume of possible activity configurations at rest and reliably settling into a confined stimulus-driven state to allow better transmission of stimulus-related information.

Cellular mechanisms generating bursting activity in neuronal networks

An open question in neuroscience is how the temporal characteristics of bursting activity are controlled by intrinsic biophysical characteristics. We present two mechanisms organized around the cornerstone bifurcation in a 3D Hodgkin-Huxley style neuronal model. This bifurcation satisfies the criteria for both the Shilnikov blue sky catastrophe and the saddle-node bifurcation on an invariant circle (SNIC) [1-3]. The burst duration (BD) and interburst interval (IBI) increase as the inverse of the square root of the difference between the corresponding parameter and its bifurcation value. The cornerstone bifurcation also determines the stereotypical transient responses of silent and spiking neurons [3]. The mechanisms presented here are based on these transient responses. The first mechanism described half-center oscillator consisting of two intrinsically silent, mutually inhibitory neurons (Figure 1AB). These two neurons were in the silent parameter regime but close to the cornerstone bifurcation. The two coupled neurons showed anti-phase bursting activity without the release and escape mechanisms. We found that if the half-activation voltage of a non-inactivating potassium current (V1/2,mk2) was systematically shifted towards the bifurcation value for the saddle-node bifurcation of periodic orbits, the BDs of both neurons increased in accordance with the inverse-square-root law and exhibited linear dependence on the spike number per burst. Figure 1 The cornerstone bifurcation generates mechanisms controlling bursting in neural networks. (A). Two endogenously silent, mutually inhibitory coupled neurons produce alternating bursting activity. V1/2,mk2 controls BDs. (B). The BDs are depicted as blue ... The second mechanism described the bursting activity of two intrinsically spiking, mutually excitatory neurons. The parameters of the neurons were in vicinity of the cornerstone bifurcation. This network exhibited synchronized bursting (Figure 1CD). Remarkably, excitatory interaction between endogenously spiking neurons essentially led to reduction of excitability of the network. When the half-activation voltage of hyperpolarization-activated current (V1/2,mh) was systematically shifted to the bifurcation value, IBIs of both neurons increased in accordance with the inverse-square-root law and the BDs and the number of spikes per burst stayed constant (6 spikes per burst). This study reveals new mechanisms controlling bursting activity in small neuronal networks based on cellular properties determining transient responses of endogenously spiking and silent neurons. These mechanisms are generic and could govern the bursting regimes in rhythmic neuronal network such as central pattern generators.

Variational Bayesian causal connectivity analysis for fMRI

The ability to accurately estimate effective connectivity among brain regions from neuroimaging data could help answering many open questions in neuroscience. We propose a method which uses causality to obtain a measure of effective connectivity from fMRI data. The method uses a vector autoregressive model for the latent variables describing neuronal activity in combination with a linear observation model based on a convolution with a hemodynamic response function. Due to the employed modeling, it is possible to efficiently estimate all latent variables of the model using a variational Bayesian inference algorithm. The computational efficiency of the method enables us to apply it to large scale problems with high sampling rates and several hundred regions of interest. We use a comprehensive empirical evaluation with synthetic and real fMRI data to evaluate the performance of our method under various conditions.

Open questions on the mechanisms of neuromodulation with applied and endogenous electric fields.

Despite a long-standing recognition that bioelectric phenomena underpin brain function, fundamental questions remain about how extracellular current flow may influence neural activity and computation. The source of extracellular current flow may be exogenous, electrical exposure or stimulation, or the source may be endogenous, for currents produced by the brain itself. The former has recently gained increased urgency with the evolution of transcranial electrical therapy for a broad range of neurological and psychiatric disorders. The latter remains one of the longest standing open questions in neuroscience—is the electrical current flow that is a ubiquitous aspect of brain function (manifest for example in oscillations, EEG) an epiphenomenon or a key functional signal in the brain. Field effects that are produced by transmembrane currents are called ephaptic. An ephapse “Gr: touching across” was originally coined to describe how two axons placed close together in mineral oil, which has a higher resistance than saline, transmit an action potential at what can be considered an artificial synapse (Katz and Schmitt, 1940; Arvanitaki, 1942). This finding led Sir John Eccles to propose the Golgi cell theory of inhibition in which he speculated that ephapses could mediate inhibitory neurotransmission (Brooks and Eccles, 1947). Eccles corrected this theory and was awarded a Nobel Prize for his subsequent work demonstrating that inhibitory neurotransmission is mediated by chemical synapses. However, in accord with Eccles original theory, ephaptic transmission has been found to mediate inhibitory neurotransmission at the Mauthner cell axon hillock (Weiss et al., 2008), and the Pinceau of the cerebellar Purkinje cell (Korn and Axelrad, 1980; Blot and Barbour, 2014). Research during the twenty-first century has demonstrated that field effects in the mammalian brain may be much more ubiquitous. Field effects generated by endogenous activity may influence network oscillations and computation throughout the cerebral cortex (Radman et al., 2007). Both physiologic (e.g., oscillations; Parra and Bikson, 2004) and pathologic (e.g., epilepsy; Haas and Jefferys, 1984) activity may be influenced by field effects. Because field effects are both generated by coherent population activity and influence networks in a coherent fashion, they may influence brain function as no neurotransmitter can. Furthermore, weak direct and alternating current stimulation of the human cerebral cortex at low-intensity strengths have been found to influence network dynamics and behavior. The exploration of transcranial Direct Current Stimulation (tDCS) and transcranial Alternative Current Stimulation (tACS) over the past decade for both treatment and to enhance cognitive performance and learning in healthy individuals, has galvanized questions about how the brain responds to low-intensity stimulation. Indeed, the intensity of electric generated in these modalities can approximate the intensity of electricity generated by the bran itself (Datta et al., 2009). Thus the science of field-effects and low-intensity electrotherapy overlap. The articles included in this e-book highlight some of the latest developments in understanding both endogenous field effects in the central nervous system, as well as the mechanisms and clinical applications of transcranial stimulation of the cortex. We hope that these articles are helpful for students, researchers, and clinicians who hope to better understand and utilize this often overlooked form of neurotransmission. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Parsing a perceptual decision into a sequence of moments of thought

Theoretical, computational, and experimental studies have converged to a model of decision-making in which sensory evidence is stochastically integrated to a threshold, implementing a shift from an analog to a discrete form of computation. Understanding how this process can be chained and sequenced – as virtually all real-life tasks involve a sequence of decisions – remains an open question in neuroscience. We reasoned that incorporating a virtual continuum of possible behavioral outcomes in a simple decision task – a fundamental ingredient of real-life decision-making – should result in a progressive sequential approximation to the correct response. We used real-time tracking of motor action in a decision task, as a measure of cognitive states reflecting an internal decision process. We found that response trajectories were spontaneously segmented into a discrete sequence of explorations separated by brief stops (about 200 ms) – which remained unconscious to the participants. The characteristics of these stops were indicative of a decision process – a “moment of thought”: their duration correlated with the difficulty of the decision and with the efficiency of the subsequent exploration. Our findings suggest that simple navigation in an abstract space involves a discrete sequence of explorations and stops and, moreover, that these stops reveal a fingerprint of moments of thought.

Brain banking: opportunities, challenges and meaning for the future

Brain banks collect post-mortem human brains to foster research into human CNS function and disease. They have been indispensable for uncovering the secrets of many diseases, including Alzheimer's and Parkinson's. At a time when there are so many open questions in neuroscience and the incidence of brain diseases continues to increase in parallel with the aging of the population, brain banking remains at the heart of brain research. However, the major source of brain banks, the clinical autopsy, is rapidly falling into limbo. New strategies, including donor programmes, medico-legal autopsies and banking in networks, as well as fresh considerations of the ethics and public relations, are required.