The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice

Investigating neurovascular coupling in awake rodents is becoming ever more popular due, in part, to our increasing knowledge of the profound impacts that anaesthesia can have upon brain physiology. Although awake imaging brings with it many advantages, we still do not fully understand how voluntary locomotion during imaging affects sensory-evoked haemodynamic responses. In this study we investigated how evoked haemodynamic responses can be affected by the amount and timing of locomotion. Using an awake imaging set up, we used 2D-Optical Imaging Spectroscopy (2D-OIS) to measure changes in cerebral haemodynamics within the sensory cortex of the brain during either 2s whisker stimulation or spontaneous (no whisker stimulation) experiments, whilst animals could walk on a spherical treadmill. We show that locomotion alters haemodynamic responses. The amount and timing of locomotion relative to whisker stimulation is important, and can significantly impact sensory-evoked haemodynamic responses. If locomotion occurred before or during whisker stimulation, the amplitude of the stimulus-evoked haemodynamic response was significantly altered. Therefore, monitoring of locomotion during awake imaging is necessary to ensure that conclusions based on comparisons of evoked haemodynamic responses (e.g., between control and disease groups) are not confounded by the effects of locomotion.

The molecular characterization of antibody binding to a superantigen-like protein from a commensal microbe

Microorganisms have coevolved diverse mechanisms to impair host defenses. A major one, superantigens, can result in devastating effects on the immune system. While all known superantigens induce vast immune cell proliferation and come from opportunistic pathogens, recently, proteins with similar broad specificity to antibody variable (V) domain families were identified in a commensal microbiota. These proteins, identified in the human commensal Ruminococcus gnavus, are called immunoglobulin-binding protein (Ibp) A and B and have been shown to activate B cells in vitro expressing either human VH3 or murine VH5/6/7. Here, we provide molecular and functional studies revealing the basis of this Ibp/immunoglobulin (Ig) interaction. The crystal structure and biochemical assays of a truncated IbpA construct in complex with mouse VH5 antigen-binding fragment (Fab) shows a binding of Ig heavy chain framework residues to the Ibp Domain D and the C-terminal heavy chain binding domain (HCBD). We used targeted mutagenesis of contact residues and affinity measurements and performed studies of the Fab-IbpA complex to determine the stoichiometry between Ibp and VH domains, suggesting Ibp may serve to cluster full-length IgA antibodies in vivo. Furthermore, in vitro stimulation experiments indicate that binding of the Ibp HCBD alone is sufficient to activate responsive murine B cell receptors. The presence of these proteins in a commensal microbe suggest that binding a broad repertoire of immunoglobulins, particularly in the gut/microbiome environment, may provide an important function in the maintenance of host/microbiome homeostasis contrasting with the pathogenic role of structurally homologous superantigens expressed by pathogens.

Induced Seismicity Completeness Analysis for Improved Data Mining

The study of induced seismicity at sites of fluid injection is paramount to assess the seismic response of the earth’s crust and to mitigate the potential seismic risk. However statistical analysis is limited to events above the completeness magnitude mc, which estimation may significantly vary depending on the employed method. To avoid potential biases and optimize the data exploitable for analysis, a better understanding of completeness, detection capacity and censored data characteristics is needed. We apply various methods previously developed for natural seismicity on 16 underground stimulation experiments. We verify that different techniques yield different mc values and we suggest using the 90% quantile of the mc distribution obtained from high-resolution mapping, with mc defined from the mode of local magnitude frequency distributions (MFD). We show that this distribution can be described by an asymmetrical Laplace distribution and the bulk MFD by an asymmetric Laplace mixture model. We obtain an averaged Gutenberg-Richter parameter b=1.03±0.48 and a detection parameter k=3.18±1.97 from mapping, with values subject to high uncertainties across stimulations. We transfer Bayesian mc mapping developed for natural seismicity to the context of induced seismicity, here adapted to local three-dimensional seismicity clouds. We obtain the new prior parameterization mc,pred=1.64log10(d3)−1.83, with d3 the distance to the 3rd nearest seismic station. The potential use of censored data and of mc prediction is finally discussed in terms of data mining to improve the monitoring, modeling and managing of induced seismicity.

Inferring Causality from Noninvasive Brain Stimulation in Cognitive Neuroscience

Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation or transcranial direct and alternating current stimulation, are advocated as measures to enable causal inference in cognitive neuroscience experiments. Transcending the limitations of purely correlative neuroimaging measures and experimental sensory stimulation, they allow to experimentally manipulate brain activity and study its consequences for perception, cognition, and eventually, behavior. Although this is true in principle, particular caution is advised when interpreting brain stimulation experiments in a causal manner. Research hypotheses are often oversimplified, disregarding the underlying (implicitly assumed) complex chain of causation, namely, that the stimulation technique has to generate an electric field in the brain tissue, which then evokes or modulates neuronal activity both locally in the target region and in connected remote sites of the network, which in consequence affects the cognitive function of interest and eventually results in a change of the behavioral measure. Importantly, every link in this causal chain of effects can be confounded by several factors that have to be experimentally eliminated or controlled to attribute the observed results to their assumed cause. This is complicated by the fact that many of the mediating and confounding variables are not directly observable and dose–response relationships are often nonlinear. We will walk the reader through the chain of causation for a generic cognitive neuroscience NIBS study, discuss possible confounds, and advise appropriate control conditions. If crucial assumptions are explicitly tested (where possible) and confounds are experimentally well controlled, NIBS can indeed reveal cause–effect relationships in cognitive neuroscience studies.

The Effect of GABAA Receptor on Information Capacity of Cultured Hippocampal Neurons

Neural information is encoded by action potentials delivered by neurons. Which component of neural activity constitutes the basic unit carrying information is still a controversial issue. In this paper, stimulation experiments using a network of hippocampal neurons cultured on a multi-electrode array are used to investigate this issue. The results show that for a set of pulse stimuli with varying voltage amplitude, the neuronal response to the fronto-potential sequence encodes more information through the moment of fronto-potential delivery than the number of fronto-potential deliveries, and that neurons at each locus are encoded independently of each other. After the addition of bicuculline inhibited the GABAA receptors, the information capacity decreased and the temporal resolution decreased, but the neurons at each site were still encoded independently. The results suggest that the encoding of stimulus amplitude in the cultured hippocampal neuronal network is better with spike timing than with count, and the effect of timing encoding is dependent on GABAA receptors.

Sensory stimulation enhances phantom limb perception and movement decoding

ObjectiveA major challenge for controlling a prosthetic arm is communication between the device and the user’s phantom limb. We show the ability to enhance amputees’ phantom limb perception and improve movement decoding through targeted transcutaneous electrical nerve stimulation (tTENS).ApproachTranscutaneous nerve stimulation experiments were performed with four amputee participants to map phantom limb perception. We measured myoelectric signals during phantom hand movements before and after amputees received sensory stimulation. Using electroencephalogram (EEG) monitoring, we measure the neural activity in sensorimotor regions during phantom movements and stimulation. In one participant, we also tracked sensory mapping over 2 years and movement decoding performance over 1 year.Main resultsResults show improvements in the amputees’ ability to perceive and move the phantom hand as a result of sensory stimulation, which leads to improved movement decoding. In the extended study with one amputee, we found that sensory mapping remains stable over 2 years. Remarkably, sensory stimulation improves within-day movement decoding while performance remains stable over 1 year. From the EEG, we observed cortical correlates of sensorimotor integration and increased motor-related neural activity as a result of enhanced phantom limb perception.SignificanceThis work demonstrates that phantom limb perception influences prosthesis control and can benefit from targeted nerve stimulation. These findings have implications for improving prosthesis usability and function due to a heightened sense of the phantom hand.

Radixin modulates stereocilia function and contributes to cochlear amplification

The stereocilia of the sensory cells in the inner ear contain high levels of the actin-binding protein radixin, encoded by the RDX gene. Radixin which is associated with mechanotransduction process such as PIP2 is known to be important for hearing but its functional role remains obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to directly visualize stereocilia motion while measuring the amplitude of the electrical potentials produced by sensory cells during acoustic stimulation. Experiments were performed in guinea pigs, where upon blocking radixin, a large decrease in sound-evoked electrical potentials occurred. Despite this decrease other important functional measures, such as electrically induced sensory cell motility and the sound-evoked deflections of stereocilia, showed a minor amplitude increase. This unique set of functional properties alterations demonstrate that radixin is necessary to ensure that the inner ear converts sound into electrical signals at acoustic rates. Radixin is therefore a necessary and important component of the cochlear amplifier, the energy-consuming process that boosts hearing sensitivity by up to 60 dB.

Unfold: an integrated toolbox for overlap correction, non-linear modeling, and regression-based EEG analysis

Electrophysiological research with event-related brain potentials (ERPs) is increasingly moving from simple, strictly orthogonal stimulation paradigms towards more complex, quasi-experimental designs and naturalistic situations that involve fast, multisensory stimulation and complex motor behavior. As a result, electrophysiological responses from subsequent events often overlap with each other. In addition, the recorded neural activity is typically modulated by numerous covariates, which influence the measured responses in a linear or non-linear fashion. Examples of paradigms where systematic temporal overlap variations and low-level confounds between conditions cannot be avoided include combined electroencephalogram (EEG)/eye-tracking experiments during natural vision, fast multisensory stimulation experiments, and mobile brain/body imaging studies. However, even “traditional,” highly controlled ERP datasets often contain a hidden mix of overlapping activity (e.g., from stimulus onsets, involuntary microsaccades, or button presses) and it is helpful or even necessary to disentangle these components for a correct interpretation of the results. In this paper, we introduce unfold, a powerful, yet easy-to-use MATLAB toolbox for regression-based EEG analyses that combines existing concepts of massive univariate modeling (“regression-ERPs”), linear deconvolution modeling, and non-linear modeling with the generalized additive model into one coherent and flexible analysis framework. The toolbox is modular, compatible with EEGLAB and can handle even large datasets efficiently. It also includes advanced options for regularization and the use of temporal basis functions (e.g., Fourier sets). We illustrate the advantages of this approach for simulated data as well as data from a standard face recognition experiment. In addition to traditional and non-conventional EEG/ERP designs, unfold can also be applied to other overlapping physiological signals, such as pupillary or electrodermal responses. It is available as open-source software at http://www.unfoldtoolbox.org.

Vesicular Antipsychotic Drug Release Evokes an Extra Phase of Dopamine Transmission

Many psychiatric drugs are weak bases that accumulate in and are released from synaptic vesicles, but the functional impact of vesicular drug release is largely unknown. Here, we examine the effect of vesicular release of the anxiolytic antipsychotic drug cyamemazine on electrically evoked striatal dopamine responses with fast scan cyclic voltammetry. Remarkably, in the presence of nanomolar extracellular cyamemazine, vesicular cyamemazine release in the brain slice can increase dopamine responses 30-fold. Kinetic analysis and multiple stimulation experiments show that this occurs by inducing delayed emptying of the releasable dopamine pool. Also consistent with increased dopamine release, an antagonist (dihydro-β-erythroidine) implicates nicotinic acetylcholine receptors, which can directly cause dopamine release, in the vesicular cyamemazine effect. Therefore, vesicular release of cyamemazine can dramatically enhance dopaminergic synaptic transmission, possibly by recruiting an excitatory cholinergic input to induce an extra phase of release. More generally, this study suggests that synaptic drug release following vesicular accumulation by acidic trapping can expand psychiatric drug pharmacodynamics.