Propagation Delays Across Cardiac Gap Junctions and their Reflection in Extracellular Potentials: A Simulation Study

This paper presents combined experimental-theoretical results pertinent to anisotropic discontinuous propagation at a microscopic size scale (<200 μm). We first simulated how the transmembrane and extracellular potential waveforms, and their derivatives, are theoretically related to each other and to the sodium current and conductance in normal propagating action potentials and at the site of a collision or end of a one-dimensional cable. We then applied the relationships between the time derivatives of the extracellular waveforms and the underlying action potentials in an experimental analysis of anisotropic propagation at this small size scale in human atrial muscle bundles of different ages. At sites where the boundary effects alter the rate of rise of the action potential, the time course of the internal membrane variables (gNa and INa) are changed in a way that alters the total open time of the sodium channels during depolarization. In turn, this predicts that the same concentration of sodium channel blocking drugs should have an anisotropic distribution in the depression of \({\dot{\text{V}}_{\text{max}}}\) and conduction velocity, a prediction confirmed with preliminary experiments. The extracellular waveforms changed from a smooth contour during transverse propagation in young preparations to complex polyphasic waveforms in the older preparations. The differences in the extracellular waveforms and their derivatives indicated that there was electrical uncoupling of the side-to-side connections between small groups of fibers with aging. These changes produced a prominent zigzag course of transverse propagation at a microscopic level which, in turn, accounted for the marked complexity of the extracellular waveforms. The electrophysiological consequence was an age-related decrease in the ‘effective’ transverse conduction velocities to the range of very slow conduction which makes it possible for reentry to occur in small regions of cardiac muscle with normal cellular electrophysiological properties.

This personal reflection that celebrates the 50th anniversary of Circulation Research focuses on an area of integrative electrophysiology—the extension of continuous medium theory to the discontinuous nature of cardiac propagation produced by the cellular interconnections (gap junctions). It is appropriate to note that as a clinician who shifted to the laboratory, my collaboration with Drs Roger Barr, J. Francis Heidlage, and Paul Dolber has provided me long-term training and checks on ideas that involve conduction theory, computer modeling, and cardiac architecture. That process has been particularly influenced by advances in this field that involve the measurement and mathematical modeling of ionic channel currents, as well as the immunohistological targeting of cardiac gap junction connexins. Although journal references are not used here, I have felt compelled to mention a few scientists who advanced selected ideas about the spread of currents in cardiac muscle. It is noteworthy that the widespread use of optical mapping to measure spiral waves that represent the behavior of cardiac wavefronts at a macroscopic size scale illustrates the contemporary importance of continuous medium theory. Interestingly, van Cappele first described complex spiral wave activity for cardiac muscle in 1980 by generating a computer model of a continuous isotropic sheet. Nine years passed before this phenomenon was experimentally confirmed in cardiac muscle. With spiral waves, the nonuniformities necessary to initiate the conduction disturbances that lead to reentry are induced experimentally as repolarization inhomogeneities (primarily by introducing stimuli at two different sites). Spiral waves are mentioned at the outset because the concept of spiral waves at a macroscopic level and the concept of discontinuous conduction at a microscopic level have both gained acceptance during the past two decades as paradigms for mechanisms of cardiac arrhythmias. Thus, it may be of interest to the reader to consider how experiments done in the …

Sevoflurane-induced loss of consciousness is paralleled by a prominent modification of neural activity during cortical down-states

GCaMP6f is among the most widely used genetically encoded calcium indicators for monitoring neuronal activity. Applications are at both the cellular and population levels. Here, we explore two important and under-explored issues. First, we have tested if GCaMP6f is sensitive enough for the detection of population activity with sparse firing, similar to the sensitivity of the local field potential (LFP). Second, we have tested if GCaMP6f is fast enough for the detection of fast network oscillations critical for the encoding and consolidation of memory. We have focused this study on the activity of the hippocampal network including sharp waves (SWs), carbachol-induced theta oscillations, and interictal-like spikes. We compare simultaneous LFP and optical GCaMP6f fluorescent recordings in Thy1-GCaMP6f mouse hippocampal slices. We observe that SWs produce a clear population GCaMP6f signal above noise with an average magnitude of 0.3% ΔF/F. This population signal is highly correlated with the LFP, albeit with a delay of 40.3 ms (SD 10.8 ms). The population GCaMP6f signal follows the LFP evoked by 20 Hz stimulation with high fidelity, while electrically evoked oscillations up to 40 Hz were detectable with reduced amplitude. GCaMP6f and LFP signals showed a large amplitude discrepancy. The amplitude of GCaMP6f fluorescence increased by a factor of 28.9 (SD 13.5) between spontaneous SWs and carbachol-induced theta bursts, while the LFP amplitude increased by a factor of 2.4 (SD 1.0). Our results suggest that GCaMP6f is a useful tool for applications commonly considered beyond the scope of genetically encoded calcium indicators. In particular, population GCaMP6f signals are sensitive enough for detecting synchronous network events with sparse firing and sub-threshold activity, as well as asynchronous events with only a nominal LFP. In addition, population GCaMP6f signals are fast enough for monitoring theta and beta oscillations (<25 Hz). Faster calcium indicators (e.g., GCaMP7) will further improve the frequency response for the detection of gamma band oscillations. The advantage of population optical over LFP recordings are that they are non-contact and free from stimulation artifacts. These features may be particularly useful for high-throughput recordings and applications sensitive to stimulus artifact, such as monitoring responses during continuous stimulation.

Local field potentials (LFPs) sampled with extracellular electrodes are frequently used as a measure of population neuronal activity. However, relating such measurements to underlying neuronal behaviour and connectivity is non-trivial. To help study this link, we developed the Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX). We first identified a reduced neuron model that retained the spatial and frequency filtering characteristics of extracellular potentials from neocortical neurons. We then developed VERTEX as an easy-to-use Matlab tool for simulating LFPs from large populations (>100,000 neurons). A VERTEX-based simulation successfully reproduced features of the LFPs from an in vitro multi-electrode array recording of macaque neocortical tissue. Our model, with virtual electrodes placed anywhere in 3D, allows direct comparisons with the in vitro recording setup. We envisage that VERTEX will stimulate experimentalists, clinicians, and computational neuroscientists to use models to understand the mechanisms underlying measured brain dynamics in health and disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0793-x) contains supplementary material, which is available to authorized users.

Optical coherence tomography (OCT) with microscopic resolution is suited for the investigation of dynamic processes on cellular level. Most existing setups for microscopic OCT (mOCT) are able to acquire A-Scans at 100 kHz, hence they are suitable for displaying only B-Scans in real-time. We present an mOCT setup with a new high-speed spectrometer, which is capable of acquiring up to 600.000 A-scans/s. Customized software allows to image mOCT volumes with micrometer resolution at video rate. Therefore, we are able to visualize functional processes on a cellular level in three dimensions over time. Here, we present 2D and 4D data of ex vivo human lung. Recording tens of high-resolution OCT volumes per seconds becomes possible faster than previous setup for OCT with microscopic resolution.

Objective. Needle electromyography (EMG) is used to study the electrical behavior of myofiber properties in patients with neuromuscular disorders. However, due to the complexity of electrical potential spatial propagation in nonhomogeneous diseased muscle, a comprehensive understanding of volume conduction effects remains elusive. Here, we develop a framework to study the conduction effect of extracellular abnormalities and electrode positioning on extracellular local field potential (LFP) recordings. Methods. The framework describes the macroscopic conduction of electrical potential in an isotropic, nonhomogeneous (i.e. two tissue) model. Numerical and finite element model simulations are provided to study the conduction effect in prototypical monopolar EMG measurements. Results. LFPs recorded are influenced in amplitude, phase and duration by the electrode position in regards to the vicinity of tissue with different electrical properties. Conclusion. The framework reveals the influence of multiple mechanisms affecting LFPs including changes in the distance between the source–electrode and tissue electrical properties. Clinical significance. Our modeled predictions may lead to new ways for interpreting volume conduction effects on recorded EMG activity, for example in neuromuscular diseases that cause structural and compositional changes in muscle tissue. These change will manifest itself by changing the electric properties of the conductor media and will impact recorded potentials in the area of affected tissue.

The extreme conditions under which multi-hop underwater acoustic sensor networks (UASNs) operate constrain the performance of medium access control (MAC) protocols. The MAC protocol employed significantly impacts the operation of the network supported, and such impacts must be carefully considered when developing protocols for networks constrained by both bandwidth and propagation delay. Time-based coordination, such as TDMA, have limited applicability due to the dynamic nature of the water channel used to propagate the sound signals, as well as the significant effect of relatively small changes in propagation distance on the propagation time. These effects cause inaccurate time synchronization and therefore make time-based access protocols less viable. The large propagation delays also diminish the effectiveness of carrier sense protocols as they do not predict with any certainty the status of the intended recipients at the point when the traffic would arrive. Thus, CSMA protocols do not perform well in UASNs, either. Reservation-based protocols have seldom been successful in commercial products over the past 50 years due to many drawbacks, such as limited scalability, relatively low robustness, etc. In particular, the impact of propagation delays in UASNs and other such constrained networks obfuscate the operation of the reservation protocols and diminish, if not completely negate, the benefit of reservations. The efficacy of the well-known RTS-CTS scheme, as a reservation-based enhancement to the CSMA protocol, is also adversely impacted by long propagation delays. An alternative to these MAC protocols is the much less complex ALOHA protocol, or one of its variants. However, the performance of such protocols within the context of multi-hop networks is not well studied. In this paper we identify the challenges of modeling contention-based MAC protocols and present models for analyzing ALOHA and p-persistent ALOHA variants for a simple string topology. As expected, an application of the model suggests that ALOHA variants are very sensitive to traffic loads. Indeed, when the traffic load is small, utilization becomes insensible to p values. A key finding, though, is the significance of the network size on the protocols' performance, in terms of successful delivery of traffic from outlying nodes, indicating that such protocols are only appropriate for very small networks, as measured by hop count.

A design methodology for sequential logic circuits using controllable flip-flops is proposed. The flip-flop setup time and propagation delay is controlled with a process, voltage and temperature (PVT) detector using an additional setup time and delay control (SDC) input. With this SDC enable, it is possible to enhance the circuit timing performance when PVT variations are detected. The PVT detector is based in the propagation delay of digital buffers. When an increase in the propagation delay is detected in the digital logic, the SDC flip-flop input is enabled to reduce its setup time and Clk-Q propagation delay. When the PVT conditions are maintained under the selected threshold, the SDC control remains disabled, saving power. The proposed flip-flop and PVT detector are designed and characterized in a TSMC 28 nm bulk CMOS technology.

A neural mass model for MEG/EEG:: coupling and neuronal dynamics

Owing to the unique characteristics of terahertz (THz) waves and their interaction with matter, THz imaging has significant potential in diverse fields, including life sciences, non-destructive quality control, and security. However, today’s THz technology faces major obstacles in providing the cost, compactness, and functional scope that is required to facilitate a wide-reaching use outside the laboratory. Therefore, the general aim of this thesis is to increase the societal impact of THz technology by exploring novel THz imaging modalities with integrated circuits (ICs) based on conventional silicon technolgy. Previous research in THz ICs mostly focused on building compact integrated source and detector components for far-field imaging systems that exploit the ability of THz waves to penetrate through diverse dielectric materials. One part of this thesis joins this research and demonstrates low-cost volumetric THz imaging based on computed tomography with silicon components for the first time. To this end, a high-power 0.43 THz source in 0.13 μm silicon-germanium heterojunction bipolar transistor (SiGe HBT) technology is developed in this thesis. However, the resolution of THz far-field imaging is limited by diffraction to the millimeter range, whereas some of the most promising THz applications in life sciences, such as intraoperative imaging of cancerous tissue, are in need for a microscopic resolution to resolve material properties on the cellular level. This thesis presents the realization of microscopic THz imaging with a silicon-based sensor system. The central contribution of this work is the development and analysis of a 128-pixel THz near-field sensor System-on-a-Chip (SoC) operating at 0.55 THz and showing a spatial resolution around 10 μm. The sensor exploits the capacitive near-field interaction between split-ring-resonator probes and imaging objects, giving an imaging contrast based on the dielectric permittivity. To simultaneously enable real-time image acquisition, high sensor sensitivity, and an integration level that is comparable to conventional consumer electronics, the full integration capabilities of a high-speed 0.13 μm SiGe bipolar CMOS (SiGe-BiCMOS) technology are exploited. In particular, the presented SoC employs cointegration of a chip-scale one-dimensional THz sensor front-end, analog signal processing, and digital circuitry for controlling the chip and external communication. The achieved results in terms of imaging speed, system cost, and integration level reach well beyond the state of the art in THz near-field imaging. The ability to rapidly acquire THz images with micrometer-scale resolution will be of benefit to fundamental research into material properties in the THz range and lays the foundation for the exploration of THz bioimaging applications on the cellular level. In particular, the sensor enables the conduction of large-scale clinical studies on the relevance of microscopic THz imaging to ex vivo tumor margin assessment in breast cancer surgeries for the first time.

Brief optogenetic stimulation of thalamocortical axons evoked a 400 Hz wavelet, 'ripplet,' in the extracellular field potential in cortical layer 4, together with phase-locked spike bursts in fast-spiking inhibitory interneurons and alternating excitatory and inhibitory synaptic currents in excitatory cells.

We examined the prognostic value of spatial and temporal characteristics of intracerebral propagation of seizures during temporal lobe epilepsy (TLE) surgery. Seven TLE patients resistant to standard anterotemporal lobectomy who had no known causes of resistance [e.g., extratemporal (ET), lesions, multifocal epilepsy] were matched with 7 seizure-free patients and 7 others who were almost seizure-free after operation. Intracerebral ictal propagation pathways were not different in the three groups. Propagation was multidirectional, most frequently to the frontal lobes and sometimes to the contralateral temporal lobe (CTL). ET propagation delays were significantly shorter in resistant patients than in markedly improved patients. The resistant group also had more frequent propagation delays < 1.0 s, but propagation times > 1.0 s were equally likely in all groups. The extent of ET propagation and frequency of focal onsets were not different among the groups. Results suggest that very short propagation times predict reduced efficacy of operation, and that long propagation times are not related to surgical success.

Measures of pulse delay in microwave propagation, in open air and for short distances (not much greater than 1 m), were made by using launcher and receiver horns. When these are facing each other we observe a delay time corresponding to a speed equal to c while, if the receiver horn is shifted or tilted with respect to the launcher horn, the delay time decreases showing a superluminal behavior. In other words the modulation phase shift, interpreted as a propagation time, turns out to be surprisingly smaller than the one relative to the light speed. This effect, which disappears for longer distances, is here interpreted on the basis of the existence of a special kind of evanescent waves (leaky waves). Just the presence of evanescent waves allows one to make a comparison with the tunneling processes where superluminal transport properties have been theoretically predicted.

A novel method for the optical testing of integrated circuits with ultrafast timeresolution and microscopic spatial resolution is described. The method is capable of detecting internal logical states switching speeds and propagation delays within complex integrated circuits as well as running times within single elements. In the experi ment a laser scanning microscope was combined with a cw modelocked argonion laser and an OBIC-stage. We achieved the complete mapping of the optical beam induced current signals in IC''s with a time resolu tion of about 100 picoseconds and a spatial resolution of less than