Mechanism Of Signal Propagation Research Articles

Graph neural network based on brain inspired forward-forward mechanism for motor imagery classification in brain-computer interfaces.

Within the development of brain-computer interface (BCI) systems, it is crucial to consider the impact of brain network dynamics and neural signal transmission mechanisms on electroencephalogram-based motor imagery (MI-EEG) tasks. However, conventional deep learning (DL) methods cannot reflect the topological relationship among electrodes, thereby hindering the effective decoding of brain activity. Inspired by the concept of brain neuronal forward-forward (F-F) mechanism, a novel DL framework based on Graph Neural Network combined forward-forward mechanism (F-FGCN) is presented. F-FGCN framework aims to enhance EEG signal decoding performance by applying functional topological relationships and signal propagation mechanism. The fusion process involves converting the multi-channel EEG into a sequence of signals and constructing a network grounded on the Pearson correlation coeffcient, effectively representing the associations between channels. Our model initially pre-trains the Graph Convolutional Network (GCN), and fine-tunes the output layer to obtain the feature vector. Moreover, the F-F model is used for advanced feature extraction and classification. Achievement of F-FGCN is assessed on the PhysioNet dataset for a four-class categorization, compared with various classical and state-of-the-art models. The learned features of the F-FGCN substantially amplify the performance of downstream classifiers, achieving the highest accuracy of 96.11% and 82.37% at the subject and group levels, respectively. Experimental results affirm the potency of FFGCN in enhancing EEG decoding performance, thus paving the way for BCI applications.

Distributed loss-amplification modeling for the mid-infrared signal propagating in the myelinated and demyelinated nerve.

The terahertz (THz) to infrared (IR) neural signal model is a potential mechanism for explaining neural communication. Myelinated neurons could be a lossy dielectric waveguide that can propagate these THz-IR neural signals. We propose an electromagnetic loss-amplification model to describe the propagation characteristics of mid-IR signals on myelinated neurons. During transmission with loss and amplification, neural signal intensity can be consistently maintained at 15.9pW in bands 55 to 75THz. This phenomenon becomes more pronounced as the number of myelin sheaths increases. However, escalated degrees of demyelination result in a reduction of signal intensity from 15.9 to 10pW. This phenomenon eventually disrupts the process of loss amplification, consequently impeding the transmission of the signal. These results may contribute to a deeper understanding of mid-IR signal propagation mechanisms in myelinated nerves and studies of diseases associated with demyelination.

Ultrafast distant wound response is essential for whole-body regeneration

Injury induces systemic responses, but their functions remain elusive. Mechanisms that can rapidly synchronize wound responses through long distances are also mostly unknown. Using planarian flatworms capable of whole-body regeneration, we report that injury induces extracellular signal-regulated kinase (Erk) activity waves to travel at a speed 10-100 times faster than those in other multicellular tissues. This ultrafast propagation requires longitudinal body-wall muscles, elongated cells forming dense parallel tracks running the length of the organism. The morphological properties of muscles allow them to act as superhighways for propagating and disseminating wound signals. Inhibiting Erk propagation prevents tissues distant to the wound from responding and blocks regeneration, which can be rescued by a second injury to distal tissues shortly after the first injury. Our findings provide a mechanism for long-range signal propagation in large, complex tissues to coordinate responses across cell types and highlight the function of feedback between spatially separated tissues during whole-body regeneration.

A Unification of LoS, Non-LoS, and Quasi-LoS Signal Propagation in Wireless Channels

The modeling of wireless communication channels is often broken down into two distinct states, defined according to the optical viewpoints of the transmitter (TX) and receiver (RX) antennas, namely, line-of-sight (LoS) and non-LoS (NLoS). Movement of the TX, RX, both and/or objects in the surrounding environment means that channel conditions may transition between LoS and NLoS leading to a third state of signal propagation, namely, quasi-LoS (QLoS). Unfortunately, this state is largely ignored in the analysis of signal propagation in wireless channels. We, therefore, propose a new statistical framework that unifies signal propagation for LoS, NLoS, and QLoS channel conditions, leading to the creation of the three-state model (TSM). The TSM has a strong physical motivation, whereby the signal propagation mechanisms underlying each state are considered to be similar to those responsible for Rician fading. However, in the TSM, the dominant signal component, if present, can be subject to shadowing. To support the use of the TSM, we develop novel formulations for the probability density functions of the in-phase and quadrature components of the complex received signal, the received signal envelope, and the received signal phase. In addition, we derive an expression for the complex autocorrelation function of the TSM, which will be of particular importance in understanding and simulating its time correlation properties. Finally, we show that the TSM provides a good fit to field measurements obtained for two different body-centric wireless channels operating at 2.45 GHz, which are known to be subject to the phenomena underlying the TSM.

Mechanisms of Vernalization-Induced Flowering in Legumes.

Vernalization is the requirement for exposure to low temperatures to trigger flowering. The best knowledge about the mechanisms of vernalization response has been accumulated for Arabidopsis and cereals. In Arabidopsis thaliana, vernalization involves an epigenetic silencing of the MADS-box gene FLOWERING LOCUS C (FLC), which is a flowering repressor. FLC silencing releases the expression of the main flowering inductor FLOWERING LOCUS T (FT), resulting in a floral transition. Remarkably, no FLC homologues have been identified in the vernalization-responsive legumes, and the mechanisms of cold-mediated transition to flowering in these species remain elusive. Nevertheless, legume FT genes have been shown to retain the function of the main vernalization signal integrators. Unlike Arabidopsis, legumes have three subclades of FT genes, which demonstrate distinct patterns of regulation with respect to environmental cues and tissue specificity. This implies complex mechanisms of vernalization signal propagation in the flowering network, that remain largely elusive. Here, for the first time, we summarize the available information on the genetic basis of cold-induced flowering in legumes with a special focus on the role of FT genes.

Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm.

Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling mechanism can be both maternal and fetal. The placental (fetal)-maternal immune and endocrine mediated homeostatic imbalances and inflammation are well reported. However, the fetal inflammatory response (FIR) theories initiated by the fetal membranes (amniochorion) at the choriodecidual interface are not well established. Although immune cell migration, activation, and production of proparturition cytokines to the fetal membranes are reported, cellular level events that can generate a unique set of inflammation are not well discussed. This review discusses derangements to fetal membrane cells (physiologically and pathologically at term and preterm, respectively) in response to both endogenous and exogenous factors to generate inflammatory signals. In addition, the mechanisms of inflammatory signal propagation (fetal signaling of parturition) and how these signals cause immune imbalances at the choriodecidual interface are discussed. In addition to maternal inflammation, this review projects FIR as an additional mediator of inflammatory overload required to promote parturition.

Bio‐Inspired 3D Artificial Neuromorphic Circuits

AbstractNeuromorphic circuits emulating the bio‐brain functionality via artificial devices have achieved a substantial scientific leap in the past decade. However, even with the advent of highly advanced bio‐inspired algorithms, the artificial intelligence based on current neuromorphic circuits is lagging behind significantly when compared with naturally evolved biological neural circuits. This massive and intriguing discrepancy is partly due to the incomprehensive understanding of bio‐brain operating mechanism, which relies heavily on the extremely complexed entangled 3D hierarchical neural networks. Configuring 3D neuromorphic hardware with combined computing and memory functionalities, coupled with compatible progress of software algorithms, can be an inevitable route to surmount the limitation encountered by current 2D artificial circuits. Herein, referring to the neuron configuration in 3D perspective together with detailed signal generation and propagation mechanism, the von Neumann configuration is compared with state‐of‐the‐art in‐memory computing architecture, and the development and perspectives of 3D in‐memory computing neuromorphic circuits are highlighted.

Quantum relaxation effects in Microtubules

The paper investigates quantum dynamics of a system of microtubule tubulins electric dipole moments. Electric dipoles represent two-level pseudo-spin systems, with one of the two polarized tubulin states corresponding to each of a pseudo-spin one. The pseudo-spin system behavior with time has been analyzed on basis of the Born–Markov formalism. The decoherence and dissipation processes caused by pseudo-spin–boson interaction have been considered. The problem of a possible signal propagation mechanism in the microtubule dipole–dipole system, which can be exclusively quantum in nature, has been discussed. It has been determined that the decoherence time depends considerably on dissipative processes in microtubules. Thus, the decoherence time in case of weak dissipation or absence of it equals 10−11–10−10 s. The decoherence time in the presence of dissipation process has been found to be 1.86⋅10−13 s. The temperature dependence of decoherence process has been considered. It has been stated that temperature values are the major factor influencing the dissipation-less decoherence time. The results obtained in the paper make it possible to describe the microtubule as a system in which quantum relaxation processes are important and comparable in time with those occurring in bio systems.

Cryo-Electron Microscopy of Arabidopsis thaliana Phytochrome A in Its Pr State Reveals Head-to-Head Homodimeric Architecture.

Phytochrome photoreceptors regulate vital adaptations of plant development, growth, and physiology depending on the ratio of red and far-red light. The light-triggered Z/E isomerization of a covalently bound bilin chromophore underlies phytochrome photoconversion between the red-absorbing Pr and far-red-absorbing Pfr states. Compared to bacterial phytochromes, the molecular mechanisms of signal propagation to the C-terminal module and its regulation are little understood in plant phytochromes, not least owing to a dearth of structural information. To address this deficit, we studied the Arabidopsis thaliana phytochrome A (AtphyA) at full length by cryo-electron microscopy (cryo-EM). Following heterologous expression in Escherichia coli, we optimized the solvent conditions to overcome protein aggregation and thus obtained photochemically active, near-homogenous AtphyA. We prepared grids for cryo-EM analysis of AtphyA in its Pr state and conducted single-particle analysis. The resulting two-dimensional class averages and the three-dimensional electron density map at 17 Å showed a homodimeric head-to-head assembly of AtphyA. Docking of domain structures into the electron density revealed a separation of the AtphyA homodimer at the junction of its photosensor and effector modules, as reflected in a large void in the middle of map. The overall architecture of AtphyA resembled that of bacterial phytochromes, thus hinting at commonalities in signal transduction and mechanism between these receptors. Our work paves the way toward future studies of the structure, light response, and interactions of full-length phytochromes by cryo-EM.

Molecular Simulations Reveal the Dynamics of the T-Cell Receptor in a T-Cell Model Membrane

The T-cell antigen receptor (TCR) initiates immune responses by recognising a wide variety of foreign peptides presented by Major Histocompatibility Complex (MHC) proteins. The TCR consists of non-covalently associated TCRαβ, CD3εγ, CD3εδ and ζζ dimers. The CD3 and ζζ subunits have long intracellular tails that regulate TCR signalling. Despite significant knowledge of the TCR structure and topology, lack of information on the arrangement of its cytoplasmic tails limits our understanding of the molecular mechanism of intracellular signal propagation in a T-cell. In this study, we used molecular modelling to model the entire TCR structure and performed multi-scale molecular dynamics simulations of the TCR embedded in a complex lipid bilayer which mimics the T-cell membrane. Our simulations revealed conformational changes within the transmembrane region of the resting TCR, and also showed that the intracellular signalling tails of CD3 and ζζ subunits fold into an intertwined conformation forming contacts with each other. Additionally, the tails strongly interacted with the inner leaflet of the membrane via cationic stretches, whilst intracellular tyrosine side-chains transiently penetrated into the hydrophobic region of the membrane. Phosphatidyl inositol phosphate (PIP) lipids and cholesterol formed preferential protein-lipid interactions creating a unique local lipid environment around the TCR. Our study provides insights into the TCR's complete structure and dynamics in a membrane in atomic resolution. Further, this potentially forms the basis to study the molecular mechanism of initiation of TCR signalling.

The not so identical twins: (dis)similarities between reactive electrophile and oxidant sensing and signaling.

In this tutorial review, we compare and contrast the chemical mechanisms of electrophile/oxidant sensing, and the molecular mechanisms of signal propagation. We critically analyze biological systems in which these different pathways are believed to be manifest and what the data really mean. Finally, we discuss applications of this knowledge to disease treatment and drug development.

Deconvolution of WNT-induced Frizzled conformational dynamics with fluorescent biosensors

The G protein-coupled receptors Frizzled1-10 (FZD1-10) act as molecular checkpoints mediating intracellular signaling induced by 19 mammalian, secreted Wingless/Int-1 lipoglycoproteins (WNTs). Despite the vital roles of these signaling components in health and disease, our knowledge about WNT/FZD selectivity, and the mechanisms of receptor activation and intracellular signal propagation by individual ligand/receptor pairs is limited due to the current lack of suitable biophysical techniques. Here, we developed fluorescence-based biosensors that detect WNT-induced FZD conformational changes in living cells in order to assess WNT action via FZDs at the most proximal level, i.e. the receptor conformation. By testing a panel of recombinant ligands on conformational biosensors representing all four homology clusters of FZDs, we discover yet unappreciated selectivities of WNTs to their receptors and, surprisingly, identify distinct ligand-induced receptor conformations. Furthermore, we demonstrate that FZDs can undergo conformational changes upon WNT binding without being dependent on the WNT co-receptors LRP5/6. This sensor toolbox provides an advanced platform for a thorough investigation of the 190 possible WNT/FZD pairings and for future screening campaigns targeting synthetic FZD ligands. Furthermore, our findings shed new light on the complexity of the WNT/FZD signaling system and have substantial implications for our understanding of fundamental biological processes including embryonal development and tumorigenesis.

Mechanism of signal uncertainty generation for laser-induced breakdown spectroscopy

Relatively large measurement uncertainty severely hindered wide application for laser-induced breakdown spectroscopy (LIBS), therefore it is of great importance to understand the mechanism of signal uncertainty generation, including initiation and propagation. It has been found that the fluctuation of plasma morphology was the main reason for signal uncertainty. However, it still remains unclear what mechanism leads to laser-induced plasma morphology fluctuation. In the present work, we employed three fast-imaging cameras to capture three successive plasma images from a same laser-induced Titanium alloy plasma, which enables us to understand more clearly of the plasma evolution process especially for the early plasma evolution stage when plasma and surrounding gases interact drastically. Seen from the images, the plasma experienced an increasing morphological fluctuation as delay time increased, transforming from a “stable plasma” before the delay time of 100 ns to a “fluctuating plasma” after the delay time of 300 ns. Notably, the frontier part of plasma showed a significant downward motion from the delay time of 150 ns to 200 ns and crashed with the lower part of the plasma, making the plasma flatter and later even splitting the plasma into two parts, which was considered as a critical process for the transformation of “stable plasma” to “unstable plasma”. By calculating the correlation coefficient of plasma image pairs at successive delay times, it was found that the higher the similarity between two plasma at early stage, the more similar at later stage; this implied that the tiny plasma fluctuation earlier than the critical delay time (150–200 ns) was amplified, causing a large plasma fluctuation at the later stage as well as LIBS measurement uncertainty. The initiation of slight fluctuation was linked with Rayleigh-Taylor Instability (RTI) due to the drastic material interpenetration at the plasma-ambient gas interface at earlier stage (before 50 ns). That is, the uncertainty generation of LIBS was proposed as: plasma morphology fluctuation was inevitably trigged by RTI at the early stage and the tiny fluctuation was amplified by the back pressed downward process of plasma frontier material, leading to severe morphology fluctuation as well as LIBS signal uncertainty.

Abstract LB-069: TRAILing chemoresistance: Oxaliplatin resistance sensitizes colorectal cancer to TRAIL via death receptor localization

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer related death in the United States. Clinical studies show combination chemotherapy cocktails increase Stage IV patient progression free survival when containing 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX). Despite an initial response rate of 40-50%, patients undergoing FOLFOX have a low median overall survival of 18-months. Treatment induced chemoresistance is in part responsible for this high morbidity, as subpopulations of surviving cells develop resistance mechanisms to induce a more aggressive, metastatic phenotype. Consequently, there exists an urgent need to develop new therapies for metastatic cancers that have become chemoresistant. We hypothesized that Tumor Necrosis factor - α Related Apoptosis Inducing Ligand (TRAIL) based therapeutics would be efficacious in treating oxaliplatin resistant CRC, providing an adjuvant for patients who have exhausted conventional treatment modalities. Four different CRC cell lines were chosen for this study: SW620, SW480, HCT116 and HT29 cells as they all have varying sensitivities to TRAIL. Briefly, oxaliplatin resistant (OxR) derivatives of these cell lines were developed by treating with oxaliplatin and subjecting surviving subpopulations to many rounds of increasing concentrations of chemotherapy. Resistant cells show increased expression of mesenchymal markers along with increased invasiveness. Metastatic CRC patient blood samples were obtained from Guthrie Clinic. Interestingly, SW620 OxR and HCT116 OxR cells show increased sensitization to soluble TRAIL compared to their parental counterparts. Flow cytometry and confocal microscopy demonstrate these sensitized cell lines have increased expression of death receptor 4 (Dr4). Previous studies have demonstrated that combination treatment with oxaliplatin and TRAIL sensitize cancer cells via localization of death receptors into lipid rafts. In our study, we observe a similar phenomenon where oxaliplatin resistant cells have a higher degree of lipid raft-Dr4 colocalization. Induction of death receptor-lipid raft complexes using resveratrol enhances parental SW620 cell sensitivity to TRAIL by 70%, whereas inhibition of lipid rafts via cholesterol sequestration using nystatin decreases sensitization of SW620 OxR cells by 30%. Circulating tumor cells (CTCs) from metastatic CRC patients who have undergone FOLOFX or oxaliplatin based chemotherapy exhibited colocalization of Dr4 and Dr5 into lipid rafts. Additionally, treating whole blood samples from patients with TRAIL-conjugated nanoparticles decreased the number of viable CTCs in circulation 4-fold compared to oxaliplatin monotherapy. These results demonstrate the utility of TRAIL based therapeutics to treat chemoresistant and metastatic CRC. Additionally, this mechanism of apoptosis signal propagation via lipid raft-death receptor complexes can be explored further to probe possible drug targets to augment receptor localization. Citation Format: Joshua Dale Greenlee, Nerymar Ortiz-Otero, Tejas Subramanian, Kevin Liu, Michael King. TRAILing chemoresistance: Oxaliplatin resistance sensitizes colorectal cancer to TRAIL via death receptor localization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-069.

Epi-Intra neural probes with glassy carbon microelectrodes help elucidate neural coding and stimulus encoding in 3D volume of tissue

Objective. In this study, we demonstrate practical applications of a novel 3-dimensional neural probe for simultaneous electrophysiological recordings from the surface of the brain as well as deep intra-cortical tissue. We used this 3D probe to investigate signal propagation mechanisms between neuronal cells and their responses to stimuli in a 3D fashion. Approach. This novel probe leverage 2D thin-film microfabrication technique to combine an epi-cortical (surface) and an intra-cortical (depth) microelectrode arrays (Epi-Intra), that unfold into an origami 3D-like probe during brain implantation. The flexible epi-cortical component conforms to the brain surface while the intra-cortical array is reinforced with stiffer durimide polymer layer for ease of tissue penetration. The microelectrodes are made of glassy carbon material that is biocompatible and has low electrochemical impedance that is important for high fidelity neuronal recordings. These recordings were performed on the auditory region of anesthetized European starling songbirds during playback of conspecific songs as auditory stimuli. Main results. The Epi-Intra probe recorded broadband activity including local field potentials (LFPs) signals as well as single-unit activity and multi-unit activity from both surface and deep brain. The majority of recorded cellular activities were stimulus-locked and exhibited low noise. Notably, while LFPs recorded on surface and depth electrodes did not exhibit strong correlation, composite receptive fields (CRFs)—extracted from individual neuron cells through a non-linear model and that are cell-dependent—were correlated. Significance. These findings demonstrate that CRFs extracted from Epi-Intra recordings are excellent candidates for neural coding and for understanding the relationship between sensory neuronal responses and their stimuli (stimulus encoding). Beyond CRFs, this novel neural probe may enable new spatiotemporal 3D volumetric mapping to address, with cellular resolution, how the brain coordinates function.

Atomic Scale Dynamics Drive Brain-like Avalanches in Percolating Nanostructured Networks.

Self-assembled networks of nanoparticles and nanowires have recently emerged as promising systems for brain-like computation. Here, we focus on percolating networks of nanoparticles which exhibit brain-like dynamics. We use a combination of experiments and simulations to show that the brain-like network dynamics emerge from atomic-scale switching dynamics inside tunnel gaps that are distributed throughout the network. The atomic-scale dynamics emulate leaky integrate and fire (LIF) mechanisms in biological neurons, leading to the generation of critical avalanches of signals. These avalanches are quantitatively the same as those observed in cortical tissue and are signatures of the correlations that are required for computation. We show that the avalanches are associated with dynamical restructuring of the networks which self-tune to balanced states consistent with self-organized criticality. Our simulations allow visualization of the network states and detailed mechanisms of signal propagation.

Strategies for identifying dynamic regions in protein complexes: Flexibility changes accompany methylation in chemotaxis receptor signaling states

Bacterial chemoreceptors are organized in arrays composed of helical receptors arranged as trimers of dimers, coupled to a histidine kinase CheA and a coupling protein CheW. Ligand binding to the external domain inhibits the kinase activity, leading to a change in the swimming behavior. Adaptation to an ongoing stimulus involves reversible methylation and demethylation of specific glutamate residues. However, the exact mechanism of signal propagation through the helical receptor to the histidine kinase remains elusive. Dynamics of the receptor cytoplasmic domain is thought to play an important role in the signal transduction, and current models propose inverse dynamic changes in different regions of the receptor. We hypothesize that the adaptational modification (methylation) controls the dynamics by stabilizing a partially ordered domain, which in turn modulates the binding of the kinase, CheA. We investigated the difference in dynamics between the methylated and unmethylated states of the chemoreceptor using solid-state NMR. The unmethylated receptor (CF4E) shows increased flexibility relative to the methylated mimic (CF4Q). Methylation helix 1 (MH1) has been shown to be flexible in the methylated mimic receptor. Our analysis indicates that in addition to MH1, methylation helix 2 also becomes flexible in the unmethylated receptor. In addition, we have demonstrated that both states of the receptor have a rigid region and segments with intermediate timescale dynamics. The strategies used in this study for identifying dynamic regions are applicable to a broad class of proteins and protein complexes with intrinsic disorder and dynamics spanning multiple timescales.

A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family.

Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The α7 subtype, in particular, has attracted considerable interest in drug discovery as a target for several conditions, including Alzheimer's disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important for understanding biological function and rational drug design. Here, extensive equilibrium and nonequilibrium molecular dynamics simulations, enabled by cloud-based high-performance computing, reveal the molecular mechanism by which structural changes induced by agonist unbinding are transmitted within the human α7 nAChR. The simulations reveal the sequence of coupled structural changes involved in driving conformational change responsible for biological function. Comparison with simulations of the α4β2 nAChR subtype identifies features of the dynamical architecture common to both receptors, suggesting a general structural mechanism for signal propagation in this important family of receptors.

Cellular and Network Mechanisms for Temporal Signal Propagation in a Cortical Network Model.

The mechanisms underlying an effective propagation of high intensity information over a background of irregular firing and response latency in cognitive processes remain unclear. Here we propose a SSCCPI circuit to address this issue. We hypothesize that when a high-intensity thalamic input triggers synchronous spike events (SSEs), dense spikes are scattered to many receiving neurons within a cortical column in layer IV, many sparse spike trains are propagated in parallel along minicolumns at a substantially high speed and finally integrated into an output spike train toward or in layer Va. We derive the sufficient conditions for an effective (fast, reliable, and precise) SSCCPI circuit: (i) SSEs are asynchronous (near synchronous); (ii) cortical columns prevent both repeatedly triggering SSEs and incorrectly synaptic connections between adjacent columns; and (iii) the propagator in interneurons is temporally complete fidelity and reliable. We encode the membrane potential responses to stimuli using the non-linear autoregressive integrated process derived by applying Newton's second law to stochastic resilience systems. We introduce a multithreshold decoder to correct encoding errors. Evidence supporting an effective SSCCPI circuit includes that for the condition, (i) time delay enhances SSEs, suggesting that response latency induces SSEs in high-intensity stimuli; irregular firing causes asynchronous SSEs; asynchronous SSEs relate to healthy neurons; and rigorous SSEs relate to brain disorders. For the condition (ii) neurons within a given minicolumn are stereotypically interconnected in the vertical dimension, which prevents repeated triggering SSEs and ensures signal parallel propagation; columnar segregation avoids incorrect synaptic connections between adjacent columns; and signal propagation across layers overwhelmingly prefers columnar direction. For the condition (iii), accumulating experimental evidence supports temporal transfer precision with millisecond fidelity and reliability in interneurons; homeostasis supports a stable fixed-point encoder by regulating changes to synaptic size, synaptic strength, and ion channel function in the membrane; together all-or-none modulation, active backpropagation, additive effects of graded potentials, and response variability functionally support the multithreshold decoder; our simulations demonstrate that the encoder-decoder is temporally complete fidelity and reliable in special intervals contained within the stable fixed-point range. Hence, the SSCCPI circuit provides a possible mechanism of effective signal propagation in cortical networks.

Pharmacological mechanisms of interhemispheric signal propagation: a TMS-EEG study.

Interhemispheric connections across the corpus callosum have a predominantly inhibitory effect. Previous electrophysiology studies imply that local inhibitory circuits are responsible for inducing transcallosal inhibition, likely through inhibitory GABAB-mediated neurotransmission. We investigated the neurochemical mechanisms involved in interhemispheric connectivity by measuring transcranial magnetic stimulation (TMS)-induced interhemispheric signal propagation (ISP) in the motor cortex and dorsolateral prefrontal cortex (DLPFC) with electroencephalography (EEG) recordings under the pharmacological effects of baclofen, L-DOPA, dextromethorphan, and rivastigmine. We hypothesized that for both stimulated regions, GABAB receptor agonist baclofen would decrease ISP when compared against baseline while drugs that target other neurotransmitter systems (dopaminergic, acetylcholinergic, and glutamatergic systems) would have no effect on ISP. Twelve right-handed healthy volunteers completed this study and underwent TMS across five sessions in a randomized order. In the motor cortex, participants showed a significant decrease in ISP under baclofen, but not in the other drug conditions. There were no drug-induced changes in ISP in the DLPFC and baseline ISP did not differ across experimental sessions for both brain regions. Together, our results suggest that the inhibitory effects observed with interhemispheric signal transmission are mediated by a population of interneurons involving GABAB receptor neurotransmission. Inhibitory mechanisms of ISP may be more salient for motor-related functions in the motor cortex than for cognitive control in the DLPFC. These findings are a fundamental step in advancing our understanding of interhemispheric connectivity and may be used to identify treatments for disorders in which transcallosal transmission is dysfunctional.