Axonal Conduction Velocity Research Articles

Widespread Associations between Behavioral Metrics and Brain Microstructure in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. A diagnosis of ASD is provided by a clinician following cognitive and behavioral evaluations, but there is currently no biomarker associating these metrics with neurological changes. Our lab has previously found that g-ratio, the proportion of axon width to myelin diameter, and axonal conduction velocity, which is associated with the capacity of an axon to carry information, are both decreased in ASD individuals. By associating these differences with performance on cognitive and behavioral tests, we can evaluate which tests most reveal changes in the brain. Analyzing 273 participants (148 with ASD) ages 8-to-17 (49% female) through an NIH-sponsored Autism Centers of Excellence (ACE) network (Grant#: MH100028), we observe widespread associations between behavioral and cognitive evaluations of autism and between behavioral and microstructural metrics. Analyzing data from all participants, conduction velocity but not g-ratio was significantly associated with many behavioral metrics. However, this pattern was reversed when looking solely at ASD participants. This reversal may suggest that the mechanism underlying differences between autistic and non-autistic individuals may be distinct from the mechanism underlying ASD behavioral severity. Two additional machine learning cluster analyses applied to neuroimaging data reinforce the association between neuroimaging and behavioral metrics and suggest that age-related maturation of brain metrics may drive changes in ASD behavior. By associating neuroimaging metrics with ASD, it may be possible to measure and identify individuals at high risk of ASD before behavioral tests can detect them.

Blocking Aδ- and C-fiber neural transmission by sub-kilohertz peripheral nerve stimulation.

We recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS). We explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz. Suprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50-1000 Hz stimulation and C-fibers blocked by 10-50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS. The current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (<100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders.

Modulation of the neuronal response in human primary visual cortex by re-entrant projections during retinal input processing as manifest in the visual evoked potential

Initial deflections in the visual evoked potential (VEP) reflect the neuronal process of extracting features from the retinal input; a process not modulated by re-entrant projections. Later deflections in the VEP reflect the neuronal process of combining features into an object, a process referred to as ‘object closure’ and modulated by re-entrant projections. Our earlier work indicated that the VEP reflects independent neuronal responses processing temporal – and spatial luminance contrast and that these responses arise from an interaction between forward and re-entrant input. In this earlier work, changing the temporal luminance contrast property of a stimulus altered its spatial luminance contrast property. We recorded the VEP in 12 volunteers viewing image pairs of a windmill, regular dartboard or an RMS dartboard rotated by either Π/4, Π/2, 3Π/4 or Π radians with respect to each other. The windmill and regular dartboard had identical white to black ratio, while the two dartboards identical contrast edges per unit area. Rotation varied temporal luminance contrast of a stimulus without affecting its spatial luminance contrast. N75, P100, N135 and P240 amplitude and latency were compared and a source localisation and temporal frequency analysis performed. P100 amplitude signals a neuronal response processing temporal luminance contrast that is modulated by re-entrant projections with fast axonal conduction velocities. N135 and P240 signal the neuronal response processing spatial luminance contrast and is modulated by re-entrant projections with slow axonal conduction velocities. The dorsal stream is interconnected by fast axonal conduction velocities, the ventral stream by slow axonal conduction velocities.

Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

Ambient sound stimulation tunes axonal conduction velocity by regulating radial growth of myelin on an individual, axon-by-axon basis

Adaptive myelination is the emerging concept of tuning axonal conduction velocity to the activity within specific neural circuits over time. Sound processing circuits exhibit structural and functional specifications to process signals with microsecond precision: a time scale that is amenable to adjustment in length and thickness of myelin. Increasing activity of auditory axons by introducing sound-evoked responses during postnatal development enhances myelin thickness, while sensory deprivation prevents such radial growth during development. When deprivation occurs during adulthood, myelin thickness was reduced. However, it is unclear whether sensory stimulation adjusts myelination in a global fashion (whole fiber bundles) or whether such adaptation occurs at the level of individual fibers. Using temporary monaural deprivation in mice provided an internal control for a) differentially tracing structural changes in active and deprived fibers and b) for monitoring neural activity in response to acoustic stimulation of the control and the deprived ear within the same animal. The data show that sound-evoked activity increased the number of myelin layers around individual active axons, even when located in mixed bundles of active and deprived fibers. Thicker myelination correlated with faster axonal conduction velocity and caused shorter auditory brainstem response wave VI-I delays, providing a physiologically relevant readout. The lack of global compensation emphasizes the importance of balanced sensory experience in both ears throughout the lifespan of an individual.

Axonal Conduction Velocity: A Computer Study

Axonal Conduction Velocity: A Computer Study

Motor Activity-Induced White Matter Repair in White Matter Stroke.

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery.

RIT1 deficiency alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

Receptive field sizes and neuronal encoding bandwidth are constrained by axonal conduction delays.

Studies on population coding implicitly assume that spikes from the presynaptic cells arrive simultaneously at the integrating neuron. In natural neuronal populations, this is usually not the case-neuronal signaling takes time and populations cover a certain space. The spread of spike arrival times depends on population size, cell density and axonal conduction velocity. Here we analyze the consequences of population size and axonal conduction delays on the stimulus encoding performance in the electrosensory system of the electric fish Apteronotus leptorhynchus. We experimentally locate p-type electroreceptor afferents along the rostro-caudal body axis and relate locations to neurophysiological response properties. In an information-theoretical approach we analyze the coding performance in homogeneous and heterogeneous populations. As expected, the amount of information increases with population size and, on average, heterogeneous populations encode better than the average same-size homogeneous population, if conduction delays are compensated for. The spread of neuronal conduction delays within a receptive field strongly degrades encoding of high-frequency stimulus components. Receptive field sizes typically found in the electrosensory lateral line lobe of A. leptorhynchus appear to be a good compromise between the spread of conduction delays and encoding performance. The limitations imposed by finite axonal conduction velocity are relevant for any converging network as is shown by model populations of LIF neurons. The bandwidth of natural stimuli and the maximum meaningful population sizes are constrained by conduction delays and may thus impact the optimal design of nervous systems.

A RhoA-mediated biomechanical response in Schwann cells modulates peripheral nerve myelination

Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional mechanical and biochemical signaling to form the myelin sheath but the mechanism underlying this process is not understood. Rho GTPases are integrators of “outside-in” signaling that link cytoskeletal dynamics with cellular architecture to regulate morphology and adhesion. Using Schwann cell-specific gene inactivation in the mouse, we discovered that RhoA promotes the initiation of myelination, and is required to both drive and terminate myelin growth at different stages of peripheral myelination, suggesting developmentally-specific modes of action. In Schwann cells, RhoA targets actin filament turnover, via Cofilin 1, actomyosin contractility and cortical actin-membrane attachments. This mechanism couples actin cortex mechanics with the molecular organization of the cell boundary to target specific signaling networks that regulate axon-Schwann cell interaction/adhesion and myelin growth. This work shows that RhoA is a key component of a biomechanical response required to control Schwann cell state transitions for proper myelination of peripheral nerves.

Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation

Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics. We hypothesized that accelerating SMA motor axon maturation would improve their function and reduce disease features. A principle regulator of peripheral axon development is neuregulin 1 type III (NRG1-III). Expressed on axon surfaces, it interacts with Schwann cell receptors to mediate axon ensheathment and myelination. We examined NRG1 mRNA and protein expression levels in human and mouse SMA tissues and observed reduced expression in SMA spinal cord and in ventral, but not dorsal root axons. To determine the impact of neuronal NRG1-III overexpression on SMA motor axon development, we bred NRG1-III overexpressing mice to SMA∆7 mice. Neonatally, elevated NRG1-III expression increased SMA ventral root size as well as axon segregation, diameter, and myelination resulting in improved motor axon conduction velocities. NRG1-III was not able to prevent distal axonal degeneration nor improve axon electrophysiology, motor behavior, or survival of older mice. Together these findings demonstrate that early SMA motor axon developmental impairments can be ameliorated by a molecular strategy independent of SMN replacement providing hope for future SMA combinatorial therapeutic approaches.

Regulation of neurofilament length and transport by a dynamic cycle of phospho-dependent polymer severing and annealing.

Neurofilaments are cargoes of axonal transport which are unique among known intracellular cargoes in that they are long, flexible protein polymers. These polymers are transported into axons, where they accumulate in large numbers to drive the expansion of axon caliber, which is an important determinant of axonal conduction velocity. We reported previously that neurofilaments can be lengthened by joining ends, called end-to-end annealing, and that they can be shortened by severing. Here, we show that neurofilament annealing and severing are robust and quantifiable phenomena in cultured neurons that act antagonistically to regulate neurofilament length. We show that this in turn regulates neurofilament transport and that severing is regulated by N-terminal phosphorylation of the neurofilament subunit proteins. We propose that focal destabilization of intermediate filaments by site-directed phosphorylation may be a general enzymatic mechanism for severing these cytoskeletal polymers, providing a mechanism to regulate the transport and accumulation of neurofilaments in axons.

Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization.

Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity, accomplished by oligodendrocytes (OLs), has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that OLs use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OLs play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL's transient intracellular responses to neural spikes is between 10 and 40 ms and the firing rates in individual axons are relatively low (10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.

Slack-based tunable damping leads to a trade-off between robustness and efficiency in legged locomotion

Animals run robustly in diverse terrain. This locomotion robustness is puzzling because axon conduction velocity is limited to a few tens of meters per second. If reflex loops deliver sensory information with significant delays, one would expect a destabilizing effect on sensorimotor control. Hence, an alternative explanation describes a hierarchical structure of low-level adaptive mechanics and high-level sensorimotor control to help mitigate the effects of transmission delays. Motivated by the concept of an adaptive mechanism triggering an immediate response, we developed a tunable physical damper system. Our mechanism combines a tendon with adjustable slackness connected to a physical damper. The slack damper allows adjustment of damping force, onset timing, effective stroke, and energy dissipation. We characterize the slack damper mechanism mounted to a legged robot controlled in open-loop mode. The robot hops vertically and planarly over varying terrains and perturbations. During forward hopping, slack-based damping improves faster perturbation recovery (up to 170%) at higher energetic cost (27%). The tunable slack mechanism auto-engages the damper during perturbations, leading to a perturbation-trigger damping, improving robustness at a minimum energetic cost. With the results from the slack damper mechanism, we propose a new functional interpretation of animals’ redundant muscle tendons as tunable dampers.

The role of neurofilament transport in the radial growth of myelinated axons.

The cross-sectional area of myelinated axons increases greatly during postnatal development in mammals and is an important influence on axonal conduction velocity. This radial growth is driven primarily by an accumulation of neurofilaments, which are cytoskeletal polymers that serve a space-filling function in axons. Neurofilaments are assembled in the neuronal cell body and transported into axons along microtubule tracks. The maturation of myelinated axons is accompanied by an increase in neurofilament gene expression and a decrease in neurofilament transport velocity, but the relative contributions of these processes to the radial growth are not known. Here, we address this question by computational modeling of the radial growth of myelinated motor axons during postnatal development in rats. We show that a single model can explain the radial growth of these axons in a manner consistent with published data on axon caliber, neurofilament and microtubule densities, and neurofilament transport kinetics in vivo. We find that the increase in the cross-sectional area of these axons is driven primarily by an increase in the influx of neurofilaments at early times and by a slowing of neurofilament transport at later times. We show that the slowing can be explained by a decline in the microtubule density.

Difference in axon diameter and myelin thickness between excitatory and inhibitory callosally projecting axons in mice.

Synchronization of network oscillation in spatially distant cortical areas is essential for normal brain activity. Precision in synchronization between hemispheres depends on the axonal conduction velocity, which is determined by physical parameters of the axons involved, including diameter, and extent of myelination. To compare these parameters in long-projecting excitatory and inhibitory axons in the corpus callosum, we used genetically modified mice and virus tracing to separately label CaMKIIα expressing excitatory and GABAergic inhibitory axons. Using electron microscopy analysis, we revealed that (i) the axon diameters of excitatory fibers (myelinated axons) are significantly larger than those of nonmyelinated excitatory axons; (ii) the diameters of bare axons of excitatory myelinated fibers are significantly larger than those of their inhibitory counterparts; and (iii) myelinated excitatory fibers are significantly larger than myelinated inhibitory fibers. Also, the thickness of myelin ensheathing inhibitory axons is significantly greater than for excitatory axons, with the ultrastructure of the myelin around excitatory and inhibitory fibers also differing. We generated a computational model to investigate the functional consequences of these parameter divergences. Our simulations indicate that impulses through inhibitory and excitatory myelinated fibers reach the targetalmost simultaneously, whereas action potentials conducted by nonmyelinated axons reach target cells with considerable delay.

Homeostatic coordination and up-regulation of neural activity by activity-dependent myelination.

Activity-dependent myelination (ADM) is a fundamental dimension of brain plasticity through which myelin changes as a function of neural activity. Mediated by structural changes in glia, ADM notably regulates axonal conduction velocity. Yet, it remains unclear how neural activity impacts myelination to orchestrate the timing of neural signalling, and how ADM shapes neural activity. We developed a model of spiking neurons enhanced with neuron-oligodendrocyte feedback and examined the relationship between ADM and neural activity. We found that ADM implements a homeostatic gain control mechanism that enhances neural firing rates and correlations through the temporal coordination of action potentials as axon lengths increase. Stimuli engage ADM plasticity to trigger bidirectional and reversible changes in conduction delays, as may occur during learning. Furthermore, ADM was found to enhance information transmission under various types of time-varying stimuli. These results highlight the role of ADM in shaping neural activity and communication.

A functional neuron maturation device provides convenient application on microelectrode array for neural network measurement

BackgroundMicroelectrode array (MEA) systems are valuable for in vitro assessment of neurotoxicity and drug efficiency. However, several difficulties such as protracted functional maturation and high experimental costs hinder the use of MEA analysis requiring human induced pluripotent stem cells (hiPSCs). Neural network functional parameters are also needed for in vitro to in vivo extrapolation.MethodsIn the present study, we produced a cost effective nanofiber culture platform, the SCAD device, for long-term culture of hiPSC-derived neurons and primary peripheral neurons. The notable advantage of SCAD device is convenient application on multiple MEA systems for neuron functional analysis.ResultsWe showed that the SCAD device could promote functional maturation of cultured hiPSC-derived neurons, and neurons responded appropriately to convulsant agents. Furthermore, we successfully analyzed parameters for in vitro to in vivo extrapolation, i.e., low-frequency components and synaptic propagation velocity of the signal, potentially reflecting neural network functions from neurons cultured on SCAD device. Finally, we measured the axonal conduction velocity of peripheral neurons. Conclusions: Neurons cultured on SCAD devices might constitute a reliable in vitro platform to investigate neuron functions, drug efficacy and toxicity, and neuropathological mechanisms by MEA.

Electrophysiological and functional signs of Guillain–Barré syndrome predicted by a multiscale neuromuscular computational model

Objective. The diagnosis of nerve disorders in humans has relied heavily on the measurement of electrical signals from nerves or muscles in response to electrical stimuli applied at appropriate locations on the body surface. The present study investigated the demyelinating subtype of Guillain–Barré syndrome using multiscale computational model simulations to verify how demyelination of peripheral axons may affect plantar flexion torque as well as the ongoing electromyogram (EMG) during voluntary isometric or isotonic contractions. Approach. Changes in axonal conduction velocities, mimicking those found in patients with the disease at different stages, were imposed on a multiscale computational neuromusculoskeletal model to simulate subjects performing unipodal plantar flexion force and position tasks. Main results. The simulated results indicated changes in the torque signal during the early phase of the disease while performing isotonic tasks, as well as in torque variability after partial conduction block while performing both isometric and isotonic tasks. Our results also indicated changes in the root mean square values and in the power spectrum of the soleus EMG signal as well as changes in the synchronization index computed from the firing times of the active motor units. All these quantitative changes in functional indicators suggest that the adoption of such additional measurements, such as torques and ongoing EMG, could be used with advantage in the diagnosis and be relevant in providing extra information for the neurologist about the level of the disease. Significance. Our findings enrich the knowledge of the possible ways demyelination affects force generation and position control during plantarflexion. Moreover, this work extends computational neuroscience to computational neurology and shows the potential of biologically compatible neuromuscular computational models in providing relevant quantitative signs that may be useful for diagnosis in the clinic, complementing the tools traditionally used in neurological electrodiagnosis.

Mathematical relationships between spinal motoneuron properties.

Our understanding of the behaviour of spinal alpha-motoneurons (MNs) in mammals partly relies on our knowledge of the relationships between MN membrane properties, such as MN size, resistance, rheobase, capacitance, time constant, axonal conduction velocity, and afterhyperpolarization duration. We reprocessed the data from 40 experimental studies in adult cat, rat, and mouse MN preparations to empirically derive a set of quantitative mathematical relationships between these MN electrophysiological and anatomical properties. This validated mathematical framework, which supports past findings that the MN membrane properties are all related to each other and clarifies the nature of their associations, is besides consistent with the Henneman's size principle and Rall's cable theory. The derived mathematical relationships provide a convenient tool for neuroscientists and experimenters to complete experimental datasets, explore the relationships between pairs of MN properties never concurrently observed in previous experiments, or investigate inter-mammalian-species variations in MN membrane properties. Using this mathematical framework, modellers can build profiles of inter-consistent MN-specific properties to scale pools of MN models, with consequences on the accuracy and the interpretability of the simulations.