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BioRxiv : the Preprint Server For... May 2024Whether the fast temporal dynamics of neural activity in brain circuits causally drive perception and cognition remains one of most longstanding unresolved questions in...
Whether the fast temporal dynamics of neural activity in brain circuits causally drive perception and cognition remains one of most longstanding unresolved questions in neuroscience . While some theories posit a 'timing code' in which dynamics on the millisecond timescale is central to brain function, others instead argue that mean firing rates over more extended periods (a 'rate code') carry most of the relevant information. Existing tools, such as optogenetics, can be used to alter temporal structure of neural dynamics , but they invariably change mean firing rates, leaving the interpretation of such experiments ambiguous. Here we developed and validated a new approach based on balanced, bidirectional optogenetics that can alter temporal structure of neural dynamics while mitigating effects on mean activity. Using this new approach, we found that selectively altering cortical temporal dynamics substantially reduced performance in a sensory perceptual task. These results demonstrate that endogenous temporal dynamics in the cortex are causally required for perception and behavior. More generally, this new bidirectional optogenetic approach should be broadly useful for disentangling the causal impact of different timescales of neural dynamics on behavior.
PubMed: 38853943
DOI: 10.1101/2024.05.30.596706 -
BioRxiv : the Preprint Server For... Jun 2024The design of bioelectronics capable of stably tracking brain-wide, single-cell, and millisecond-resolved neural activities in the developing brain is critical to the...
The design of bioelectronics capable of stably tracking brain-wide, single-cell, and millisecond-resolved neural activities in the developing brain is critical to the study of neuroscience and neurodevelopmental disorders. During development, the three-dimensional (3D) structure of the vertebrate brain arises from a 2D neural plate . These large morphological changes previously posed a challenge for implantable bioelectronics to track neural activity throughout brain development . Here, we present a tissue-level-soft, sub-micrometer-thick, stretchable mesh microelectrode array capable of integrating into the embryonic neural plate of vertebrates by leveraging the 2D-to-3D reconfiguration process of the tissue itself. Driven by the expansion and folding processes of organogenesis, the stretchable mesh electrode array deforms, stretches, and distributes throughout the entire brain, fully integrating into the 3D tissue structure. Immunostaining, gene expression analysis, and behavioral testing show no discernible impact on brain development or function. The embedded electrode array enables long-term, stable, brain-wide, single-unit-single-spike-resolved electrical mapping throughout brain development, illustrating how neural electrical activities and population dynamics emerge and evolve during brain development.
PubMed: 38853924
DOI: 10.1101/2024.05.29.596533 -
BioRxiv : the Preprint Server For... Jun 2024The auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR...
The auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR originates from the response sequence of auditory brainstem nuclei, and a click-evoked ABR typically shows three positive peaks ('waves') within the first six milliseconds. However, an assignment of the waves of the ABR to specific sources is difficult, and a quantification of contributions to the ABR waves is not available. Here, we exploit the large size and physical separation of the barn owl first-order cochlear nucleus magnocellularis (NM) to estimate single-cell contributions to the ABR. We simultaneously recorded NM neurons' spikes and the EEG, and found that > 5,000 spontaneous single-cell spikes are necessary to isolate a significant spike-triggered average response at the EEG electrode. An average single-neuron contribution to the ABR was predicted by convolving the spike-triggered average with the cell's peri-stimulus time histogram. Amplitudes of predicted contributions of single NM cells typically reached 32.9 nV (mean, range: 2.5 - 162.7 nV), or 0.07% (median, range: 0.01 - 4.0%) of the ABR amplitude. The time of the predicted peak coincided best with the peak of the ABR wave II, and this coincidence was independent of the click sound level. Our results suggest that wave II of the ABR is shaped by a small fraction of NM units.
PubMed: 38853863
DOI: 10.1101/2024.05.29.596509 -
Cortex; a Journal Devoted To the Study... May 2024Extensive research has documented the brain networks that play an integral role in bias, or the alteration and filtration of information processing in a manner that... (Review)
Review
Extensive research has documented the brain networks that play an integral role in bias, or the alteration and filtration of information processing in a manner that fundamentally favors an individual. The roots of bias, whether self- or other-oriented, are a complex constellation of neural and psychological processes that start at the most fundamental levels of sensory processing. From the millisecond information is received in the brain it is filtered at various levels and through various brain networks in relation to extant intrinsic activity to provide individuals with a perception of reality that complements and satisfies the conscious perceptions they have for themselves and the cultures in which they were reared. The products of these interactions, in turn, are dynamically altered by the introduction of others, be they friends or strangers who are similar or different in socially meaningful ways. While much is known about the various ways that basic biases alter specific aspects of neural function to support various forms of bias, the breadth and scope of the phenomenon remains entirely unclear. The purpose of this review is to examine the brain networks that shape (i.e., bias) the self-concept and how interactions with similar (ingroup) compared to dissimilar (outgroup) others alter these network (and subsequent interpersonal) interactions in fundamental ways. Throughout, focus is placed on an emerging understanding of the brain as a complex system, which suggests that many of these network interactions likely occur on a non-linear scale that blurs the lines between network hierarchies.
PubMed: 38848651
DOI: 10.1016/j.cortex.2024.05.002 -
Journal of the American Chemical Society Jun 2024We present millisecond quantitative serial X-ray crystallography at 1.7 Å resolution demonstrating precise optical control of reversible population transfer from...
Power Density Titration of Reversible Photoisomerization of a Fluorescent Protein Chromophore in the Presence of Thermally Driven Barrier Crossing Shown by Quantitative Millisecond Serial Synchrotron X-ray Crystallography.
We present millisecond quantitative serial X-ray crystallography at 1.7 Å resolution demonstrating precise optical control of reversible population transfer from Trans-Cis and Cis-Trans photoisomerization of a reversibly switchable fluorescent protein, rsKiiro. Quantitative results from the analysis of electron density differences, extrapolated structure factors, and occupancy refinements are shown to correspond to optical measurements of photoinduced population transfer and have sensitivity to a few percent in concentration differences. Millisecond time-resolved concentration differences are precisely and reversibly controlled through intense continuous wave laser illuminations at 405 and 473 nm for the Trans-to-Cis and Cis-to-Trans reactions, respectively, while the X-ray crystallographic measurement and laser illumination of the metastable Trans chromophore conformation causes partial thermally driven reconversion across a 91.5 kJ/mol thermal barrier from which a temperature jump between 112 and 128 K is extracted.
PubMed: 38848551
DOI: 10.1021/jacs.3c12883 -
JAMA Network Open Jun 2024Rifampin-resistant tuberculosis treatment regimens require electrocardiographic (ECG) monitoring due to the use of multiple QTc-prolonging agents. Formal 12-lead ECG...
IMPORTANCE
Rifampin-resistant tuberculosis treatment regimens require electrocardiographic (ECG) monitoring due to the use of multiple QTc-prolonging agents. Formal 12-lead ECG devices represent a significant burden in resource-constrained clinics worldwide and a potential barrier to treatment scale-up in some settings.
OBJECTIVE
To evaluate the diagnostic accuracy of a handheld 6-lead ECG device within resource-constrained clinics.
DESIGN, SETTING, AND PARTICIPANTS
This diagnostic study was performed within a multicenter, pragmatic (broad eligibility criteria with no exclusions for randomized participants), phase 3 rifampin-resistant tuberculosis treatment trial (BEAT Tuberculosis [Building Evidence for Advancing New Treatment for Tuberculosis]) in South Africa. A total of 192 consecutive trial participants were assessed, and 191 were recruited for this substudy between January 21, 2021, and March 27, 2023. A low proportion (3 of 432 [0.7%]) of all screened trial participants were excluded due to a QTc interval greater than 450 milliseconds. Triplicate reference standard 12-lead ECG results were human calibrated with readers blinded to 6-lead ECG results.
MAIN OUTCOMES AND MEASURES
Diagnostic accuracy, repeatability, and feasibility of a 6-lead ECG device.
RESULTS
A total of 191 participants (median age, 36 years [IQR, 28-45 years]; 81 female participants [42.4%]; 91 participants [47.6%] living with HIV) with a median of 4 clinic visits (IQR, 3-4 visits) contributed 2070 and 2015 12-lead and 6-lead ECG assessments, respectively. Across 170 participants attending 489 total clinic visits where valid triplicate QTc measurements were available for both devices, the mean 12-lead QTc measurement was 418 milliseconds (range, 321-519 milliseconds), and the mean 6-lead QTc measurement was 422 milliseconds (range, 288-574 milliseconds; proportion of variation explained, R2 = 0.4; P < .001). At a QTc interval threshold of 500 milliseconds, the 6-lead ECG device had a negative predictive value of 99.8% (95% CI, 98.8%-99.9%) and a positive predictive value of 16.7% (95% CI, 0.4%-64.1%). The normal expected range of within-individual variability of the 6-lead ECG device was high (±50.2 milliseconds [coefficient of variation, 6.0%]) relative to the 12-lead ECG device (±22.0 milliseconds [coefficient of variation, 2.7%]). The mean (SD) increase in the 12-lead QTc measurement during treatment was 10.1 (25.8) milliseconds, with 0.8% of clinic visits (4 of 489) having a QTc interval of 500 milliseconds or more.
CONCLUSIONS AND RELEVANCE
This study suggests that simplified, handheld 6-lead ECG devices are effective triage tests that could reduce the need to perform 12-lead ECG monitoring in resource-constrained settings.
Topics: Humans; Female; Male; Adult; Electrocardiography; South Africa; Middle Aged; Long QT Syndrome; Reproducibility of Results; Tuberculosis, Multidrug-Resistant; Resource-Limited Settings
PubMed: 38848063
DOI: 10.1001/jamanetworkopen.2024.15576 -
Scientific Reports Jun 2024The experimental findings from the Large Helical Device have demonstrated a fast, nondiffusive behavior during the propagation of heat pulses, with an observed increase...
The experimental findings from the Large Helical Device have demonstrated a fast, nondiffusive behavior during the propagation of heat pulses, with an observed increase in speed with reduction in their temporal width. Concurrent propagation of the temperature gradient and turbulence, in a timeframe spanning from a few milliseconds to tens of milliseconds, aligned with the avalanche model. These results indicate that the more spatiotemporally localized the heat and turbulence pulses are, the greater the deviation of the plasma from its equilibrium state, coupled with faster propagation velocity. This insight is pivotal for future fusion reactors, which necessitate the maintenance of a steady-state, non-equilibrium condition.
PubMed: 38844607
DOI: 10.1038/s41598-024-63788-0 -
Neurophotonics Apr 2024The development of genetically encoded fluorescent indicators of neural activity with millisecond dynamics has generated demand for ever faster two-photon (2P) imaging...
SIGNIFICANCE
The development of genetically encoded fluorescent indicators of neural activity with millisecond dynamics has generated demand for ever faster two-photon (2P) imaging systems, but acoustic and mechanical beam scanning technologies are approaching fundamental limits. We demonstrate that potassium tantalate niobate (KTN) electro-optical deflectors (EODs), which are not subject to the same fundamental limits, are capable of ultrafast two-dimensional (2D) 2P imaging .
AIM
To determine if KTN-EODs are suitable for 2P imaging, compatible with 2D scanning, and capable of ultrafast imaging of genetically encoded indicators with millisecond dynamics.
APPROACH
The performance of a commercially available KTN-EOD was characterized across a range of drive frequencies and laser parameters relevant to 2P microscopy. A second KTN-EOD was incorporated into a dual-axis scan module, and the system was validated by imaging signals from ASAP3, a genetically encoded voltage indicator.
RESULTS
Optimal KTN-EOD deflection of laser light with a central wavelength of 960 nm was obtained up to the highest average powers and pulse intensities tested (power: 350 mW; pulse duration: 118 fs). Up to 32 resolvable spots per line at a 560 kHz line scan rate could be obtained with single-axis deflection. The complete dual-axis EO 2P microscope was capable of imaging a by field-of-view at over 10 kHz frame rate with lateral resolution. We demonstrate imaging of neurons expressing ASAP3 with high temporal resolution.
CONCLUSIONS
We demonstrate the suitability of KTN-EODs for ultrafast 2P cellular imaging , providing a foundation for future high-performance microscopes to incorporate emerging advances in KTN-based scanning technology.
PubMed: 38841422
DOI: 10.1117/1.NPh.11.2.025005 -
International Journal of Biological... Jun 2024Low molecular weight heparin and synthetic mimetics such as fondaparinux show different binding kinetics, protease specificity, and clinical effects. A combination of...
Low molecular weight heparin and synthetic mimetics such as fondaparinux show different binding kinetics, protease specificity, and clinical effects. A combination of allosteric and template-mediated bridging mechanisms have been proposed to explain the differences in rate acceleration and specificity. The difficulty in working with heterogeneous heparin species has rendered a crystallographic interpretation of the differences in antithrombin activation between mimetics and natural heparin inaccessible. In this study, we examine the allosteric changes in antithrombin caused by binding fondaparinux, enoxaparin and depolymerized natural heparins using millisecond hydrogen deuterium exchange mass spectrometry (TRESI-HDX MS) and relate these conformational changes to complex stability in the gas phase using collision induced unfolding (CIU). This exploration reveals that in addition to the dynamic changes caused by fondaparinux, long chain heparins reduce structural flexibility proximal to Arg393, the cleavable residue in the reactive centre loop of the protein. These local changes in protein dynamics are associated with an increase in overall complex stability that increases with heparin chain length. Ultimately, these results shed light on the molecular mechanisms underlying differences in activity and specificity between heparin mimetics and natural heparins.
PubMed: 38838881
DOI: 10.1016/j.ijbiomac.2024.132868 -
Light, Science & Applications Jun 2024Mechanical forces are key regulators of cellular behavior and function, affecting many fundamental biological processes such as cell migration, embryogenesis,...
Mechanical forces are key regulators of cellular behavior and function, affecting many fundamental biological processes such as cell migration, embryogenesis, immunological responses, and pathological states. Specialized force sensors and imaging techniques have been developed to quantify these otherwise invisible forces in single cells and in vivo. However, current techniques rely heavily on high-resolution microscopy and do not allow interrogation of optically dense tissue, reducing their application to 2D cell cultures and highly transparent biological tissue. Here, we introduce DEFORM, deformable microlaser force sensing, a spectroscopic technique that detects sub-nanonewton forces with unprecedented spatio-temporal resolution. DEFORM is based on the spectral analysis of laser emission from dye-doped oil microdroplets and uses the force-induced lifting of laser mode degeneracy in these droplets to detect nanometer deformations. Following validation by atomic force microscopy and development of a model that links changes in laser spectrum to applied force, DEFORM is used to measure forces in 3D and at depths of hundreds of microns within tumor spheroids and late-stage Drosophila larva. We furthermore show continuous force sensing with single-cell spatial and millisecond temporal resolution, thus paving the way for non-invasive studies of biomechanical forces in advanced stages of embryogenesis, tissue remodeling, and tumor invasion.
PubMed: 38834554
DOI: 10.1038/s41377-024-01471-9