Axonal Conduction Velocity Research Articles

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.

Maternal sevoflurane exposure disrupts oligodendrocyte myelination of the postnatal hippocampus and induces cognitive and motor impairments in offspring

Maternal exposure to anesthetic agents could impose significant neurocognitive risks on the developing brain of infants. Myelin produced by oligodendrocytes (OLs) is essential for the development of brain. However, the concrete effect of general anesthesia on the development and myelination of OLs is still elusive. In this study, we aim to investigate postnatal myelination and neural behavior after maternal exposure to sevoflurane. Pregnant C57BL/6 J mice (gestational day 15.5) were anesthetized with 2.5% sevoflurane (in 97.5% O2) for 6 h. Cognitive function and motor coordination of the offspring mice were evaluated with novel object recognition, Morris water maze and accelerating rotarod tests. Myelination and development of hippocampal OLs were analyzed with immunohistochemistry, qRT-PCR, western blotting and electron microscopy. The functionality of myelin was measured with electrophysiology. Our results showed that sevoflurane anesthesia during the gestational period induced cognitive and motor impairments in offspring mice, accompanied with damages of myelin structure and down regulations of myelin-associated genes and proteins (including MBP, Olig1, PDGFRα, Sox10, etc.). The development and maturation of OLs were suppressed, and the axonal conduction velocity was declined. These results demonstrated that maternal sevoflurane exposure could induce detrimental effects on cognitive and motor functions in offspring, which might be associated with disrupted myelination of OLs in the hippocampus.

In vivo Estimation of Axonal Morphology From Magnetic Resonance Imaging and Electroencephalography Data.

PurposeWe present a novel approach that allows the estimation of morphological features of axonal fibers from data acquired in vivo in humans. This approach allows the assessment of white matter microscopic properties non-invasively with improved specificity.TheoryThe proposed approach is based on a biophysical model of Magnetic Resonance Imaging (MRI) data and of axonal conduction velocity estimates obtained with Electroencephalography (EEG). In a white matter tract of interest, these data depend on (1) the distribution of axonal radius [P(r)] and (2) the g-ratio of the individual axons that compose this tract [g(r)]. P(r) is assumed to follow a Gamma distribution with mode and scale parameters, M and θ, and g(r) is described by a power law with parameters α and β.MethodsMRI and EEG data were recorded from 14 healthy volunteers. MRI data were collected with a 3T scanner. MRI-measured g-ratio maps were computed and sampled along the visual transcallosal tract. EEG data were recorded using a 128-lead system with a visual Poffenberg paradigm. The interhemispheric transfer time and axonal conduction velocity were computed from the EEG current density at the group level. Using the MRI and EEG measures and the proposed model, we estimated morphological properties of axons in the visual transcallosal tract.ResultsThe estimated interhemispheric transfer time was 11.72 ± 2.87 ms, leading to an average conduction velocity across subjects of 13.22 ± 1.18 m/s. Out of the 4 free parameters of the proposed model, we estimated θ – the width of the right tail of the axonal radius distribution – and β – the scaling factor of the axonal g-ratio, a measure of fiber myelination. Across subjects, the parameter θ was 0.40 ± 0.07 μm and the parameter β was 0.67 ± 0.02 μm−α.ConclusionThe estimates of axonal radius and myelination are consistent with histological findings, illustrating the feasibility of this approach. The proposed method allows the measurement of the distribution of axonal radius and myelination within a white matter tract, opening new avenues for the combined study of brain structure and function, and for in vivo histological studies of the human brain.

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.

Multisite silicon probes enable simultaneous recording of spontaneous and evoked activity in multiple isolated C-fibres in rat saphenous nerve

BackgroundRecordings of electrical activity in nerves have provided valuable insights into normal function and pathological behaviours of the nervous system. Current high-resolution techniques (e.g. teased fibre recordings) typically utilise electrodes with a single recording site, capturing the activity of a single isolated neuron per recording. New methodWe conducted proof-of-principle C-fibre recordings in the saphenous nerve of urethane-anaesthetised adult Wistar rats using 32-channel multisite silicon electrodes. Data was acquired using the OpenEphys recording system and clustered offline with Kilosort 2.5. ResultsIn single recordings in 5 rats, 32 units with conduction velocities in the C-fibre range (< 1 m/s) were identified via constant latency responses and classified using activity dependent slowing. In two animals, 6 C-fibres (5 classified as nociceptors) were well isolated after clustering. Their activity could be tracked throughout the recording – including during periods of spontaneous activity. Axonal conduction velocities were calculated from spontaneous activity and/or low frequency electrical stimulation using only the differences in action potential latency as it propagated past multiple probe sites. Comparison with existing methodsSingle electrode approaches have a low data yield and generating group data for specific fibre types is challenging as it requires multiple experimental subjects and recording sessions. This is particularly true when the experimental targets are the small, unmyelinated C-fibres carrying nociceptive information. ConclusionsWe demonstrate that multisite recordings can greatly increase experimental yields and enhance fibre identification. The approach is of particular utility when coupled with clustering analysis. Multisite probes and analysis approaches constitute a valuable new toolbox for researchers studying the peripheral nervous system.

Axonal Conduction Delay Shapes the Precision of the Spatial Hearing in A Spiking Neural Network Model of Auditory Brainstem.

One method by which the mammalian sound localization pathway localizes sound sources is by analyzing the microsecond-level difference between the arrival times of a sound at the two ears. However, how the neural circuits in the auditory brainstem precisely integrate signals from the two ears, and what the underlying mechanisms are, remains to be understood. Recent studies have reported that variations of axon myelination in the auditory brainstem produces various axonal conduction velocities and sophisticated temporal dynamics, which have not been well characterized in most existing models of sound localization circuits. Here, we present a spiking neural network model of the auditory brainstem to investigate how axon myelinations affect the precision of sound localization. Sound waves with different interaural time differences (ITDs) are encoded and used as stimuli, and the axon properties in the network are adjusted, and the corresponding axonal conduction delays are computed with a multi-compartment axon model. Through the simulation, the sensitivity of ITD perception varies with the myelin thickness of axons in the contralateral input pathways to the medial superior olive (MSO). The ITD perception becomes more precise when the contralateral inhibitory input propagates faster than the contralateral excitatory input. These results indicate that axon myelination and contralateral spike timing influence spatial hearing perception.

Dissecting whole-brain conduction delays through MRI microstructural measures

Network models based on structural connectivity have been increasingly used as the blueprint for large-scale simulations of the human brain. As the nodes of this network are distributed through the cortex and interconnected by white matter pathways with different characteristics, modeling the associated conduction delays becomes important. The goal of this study is to estimate and characterize these delays directly from the brain structure. To achieve this, we leveraged microstructural measures from a combination of advanced magnetic resonance imaging acquisitions and computed the main determinants of conduction velocity, namely axonal diameter and myelin content. Using the model proposed by Rushton, we used these measures to calculate the conduction velocity and estimated the associated delays using tractography. We observed that both the axonal diameter and conduction velocity distributions presented a rather constant trend across different connection lengths, with resulting delays that scale linearly with the connection length. Relying on insights from graph theory and Kuramoto simulations, our results support the approximation of constant conduction velocity but also show path- and region-specific differences.

Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the CNS. Myelin sheath length is a key property that determines axonal conduction velocity and is known to be variable across the CNS. Myelin sheath length can be modified by neuronal activity, suggesting that dynamic regulation of sheath length might contribute to the functional plasticity of neural circuits. Although the mechanisms that establish and refine myelin sheath length are important determinants of brain function, our understanding of these remains limited. In recent years, the membranes of myelin sheaths have been increasingly recognized to contain ion channels and transporters that are associated with specific important oligodendrocyte functions, including metabolic support of axons and the regulation of ion homeostasis, but none have been shown to influence sheath architecture. In this study, we determined that hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, typically associated with neuronal and cardiac excitability, regulate myelin sheath length. Using both in vivo and in vitro approaches, we show that oligodendrocytes abundantly express functional, predominantly HCN2 subunit-containing ion channels. These HCN ion channels retain key pharmacological and biophysical features and regulate the resting membrane potential of myelinating oligodendrocytes. Further, reduction of their function via pharmacological blockade or generation of transgenic mice with two independent oligodendrocyte-specific HCN2 knock-out strategies reduced myelin sheath length. We conclude that HCN2 ion channels are key determinants of myelin sheath length in the CNS.SIGNIFICANCE STATEMENT Myelin sheath length is a critical determinant of axonal conduction velocity, but the signaling mechanisms responsible for determining sheath length are poorly understood. Here we find that oligodendrocytes express functional hyperpolarization-activated, cyclic nucleotide-gated 2 (HCN2) ion channels that regulate the length of myelin sheaths formed by oligodendrocytes in myelinating cultures and in the mouse brain and spinal cord. These results suggest that the regulation of HCN2 channel activity is well placed to refine sheath length and conduction along myelinated axons, providing a potential mechanism for alterations in conduction velocity and circuit function in response to axonal signals such as those generated by increased activity.

Axon morphology is modulated by the local environment and impacts the noninvasive investigation of its structure–function relationship

Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Noninvasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires three-dimensional (3D) validation. Here, high-resolution, 3D synchrotron X-ray nano-holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells, and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variation in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship.

Numerical analysis of conduction velocity/path relationships in a crustacean sensory neuron.

Experimental observations of the axonal conduction velocities of sensory neurons associated with near-field sensilla on the cephalothorax of the crayfish Procambarus clarkii indicate that neurons supplying sensilla farther from their connections with the central nervous system exhibit higher overall impulse conduction velocities. The conduction velocity/distance relationship is best described by an exponentially rising, asymptotic curve. A numerical model for regional variations in impulse conduction velocity in these sensory neurons was developed, based upon neuronal morphological metrics and physiological data. The predicted relationship between conduction velocity and length of conduction pathway in the model was compared to experimental data from 88 sensory neurons associated with thoracic near-field receptor sensilla, in which both the mean conduction velocity and the length of the conduction pathway for each neuron were known. Curves fitted to the conduction velocity versus distance relationship in the two cases were similar, although not congruent. Chi-square statistics comparing the curves predict that the curves are similar at the 0.005 probability level, suggesting that the numerical model's variations in axonal morphology can satisfactorily account for the observed conduction velocity-distance relationship in these sensory neurons.

Comparison of Muscle MEPs From Transcranial Magnetic and Electrical Stimulation and Appearance of Reflexes in Horses.

IntroductionTranscranial electrical (TES) and magnetic stimulation (TMS) are both used for assessment of the motor function of the spinal cord in horses. Muscular motor evoked potentials (mMEP) were compared intra-individually for both techniques in five healthy horses. mMEPs were measured twice at increasing stimulation intensity steps over the extensor carpi radialis (ECR), tibialis cranialis (TC), and caninus muscles. Significance was set at p < 0.05. To support the hypothesis that both techniques induce extracranially elicited mMEPs, literature was also reviewed.ResultsBoth techniques show the presence of late mMEPs below the transcranial threshold appearing as extracranially elicited startle responses. The occurrence of these late mMEPs is especially important for interpretation of TMS tracings when coil misalignment can have an additional influence. Mean transcranial motor latency times (MLT; synaptic delays included) and conduction velocities (CV) of the ECR and TC were significantly different between both techniques: respectively, 4.2 and 5.5 ms (MLTTMS–-MLTTES), and −7.7 and −9.9 m/s (CVTMS-CVTES). TMS and TES show intensity-dependent latency decreases of, respectively, −2.6 (ECR) and −2.7 ms (TC)/30% magnetic intensity and −2.6 (ECR) and −3.2 (TC) ms/30V. When compared to TMS, TES shows the lowest coefficients of variation and highest reproducibility and accuracy for MLTs. This is ascribed to the fact that TES activates a lower number of cascaded interneurons, allows for multipulse stimulation, has an absence of coil repositioning errors, and has less sensitivity for varying degrees of background muscle tonus. Real axonal conduction times and conduction velocities are most closely approximated by TES.ConclusionBoth intracranial and extracranial mMEPs inevitably carry characteristics of brainstem reflexes. To avoid false interpretations, transcranial mMEPs can be identified by a stepwise latency shortening of 15–20 ms when exceeding the transcranial motor threshold at increasing stimulation intensities. A ring block around the vertex is advised to reduce interference by extracranial mMEPs. mMEPs reflect the functional integrity of the route along the brainstem nuclei, extrapyramidal motor tracts, propriospinal neurons, and motoneurons. The corticospinal tract appears subordinate in horses. TMS and TES are interchangeable for assessing the functional integrity of motor functions of the spinal cord. However, TES reveals significantly shorter MLTs, higher conduction velocities, and better reproducibility.

Transient Hypothyroidism During Lactation Alters the Development of the Corpus Callosum in Rats. An in vivo Magnetic Resonance Image and Electron Microscopy Study.

Magnetic resonance imaging (MRI) data of children with late diagnosed congenital hypothyroidism and cognitive alterations such as abnormal verbal memory processing suggest altered telencephalic commissural connections. The corpus callosum (CC) is the major inter-hemispheric commissure that contra-laterally connects neocortical areas. However, in late diagnosed neonates with congenital hypothyroidism, the possible effect of early transient and chronic postnatal hypothyroidism still remains unknown. We have studied the development of the anterior, middle and posterior CC, using in vivo MRI and electron microscopy in hypothyroid and control male rats. Four groups of methimazole (MMI) treated rats were studied. One group, as a model for early transient hypothyroidism, was MMI-treated from postnatal day (P) 0 to P21; some of these rats were also treated with L-thyroxine (T4) from P15 to 21. Another group modeling chronic hypothyroid, were treated with MMI from P0 to 150 and from embryonic day 10 to P170. The results obtained from these groups were compared with same age control rats. The normalized T2 signal obtained using MRI was higher in MMI-treated rats and correlated with a low number and percentage of myelinated axons. The number and density of myelinated axons decreased in transient and chronic hypothyroid rats at P150. The g-ratio (inner to outer diameter ratio) and the estimated conduction velocity of myelinated axons were similar between MMI-treated and controls, but the conduction delay decreased in the posterior CC of MMI-treated rats compared to controls. These data show that early postnatal transient and chronic hypothyroidism alters CC maturation in a way that may affect the callosal transfer of information. These alterations cannot be reversed after delayed T4-treatment. Our data support the findings of neurocognitive delay in late T4-treated children with congenital hypothyroidism.

White matter alterations in Williams syndrome related to behavioral and motor impairments.

Myelin is the electrical insulator surrounding the neuronal axon that makes up the white matter (WM) of the brain. It helps increase axonal conduction velocity (CV) by inducing saltatory conduction. Damage to the myelin sheath and WM is associated with many neurological and psychiatric disorders. Decreasing myelin deficits, and thus improving axonal conduction, has the potential to serve as a therapeutic mechanism for reducing the severity of some of these disorders. Myelin deficits have been previously linked to abnormalities in social behavior, suggesting an interplay between brain connectivity and sociability. This review focuses on Williams syndrome (WS), a genetic disorder characterized by neurocognitive characteristics and motor abnormalities, mainly known for its hypersociability characteristic. We discuss fundamental aspects of WM in WS and how its alterations can affect motor abilities and social behavior. Overall, findings regarding changes in myelin genes and alterations in WM structure in WS suggest new targets for drug therapy aimed at improving conduction properties and altering brain-activity synchronization in this disorder.

SPARC: Modelling a Bidirectional Bioelectric Pelvic Nerve Interface

BackgroundMicturition (urination) and continence are controlled by the autonomic nervous system; disruptions to urinary control due to disease or injury significantly impair patients’ quality‐of‐life. The pelvic nerves (in human, the pelvic splanchnic nerves) provide the primary source of autonomic sensory and motor innervation to the bladder and are prime targets for electrical stimulation to treat over‐ or under‐active bladder. The pelvic nerves in both human and rat are fasciculated, but differ from other well‐studied nerves such as the vagus or sciatic nerves in largely lacking a resistive epineurium. The pelvic nerves also comprise a much higher proportion of smaller‐caliber axons than are currently implemented in existing myelinated axon models.ObjectiveTo determine the significance of the macro‐ and micro‐anatomical properties of the pelvic nerve on the stimulation and recording performance of bioelectric neural interfaces.MethodsThe functional composition of the different fascicles of the pelvic nerve were determined using a combination of immunolabeling and tract tracing from the specific regions of the lower urinary tract or large intestine in male rats. Using this data, a model of the pelvic nerves and electrode array was implemented in SIM4LIFE (zmt.swiss) and EIDORS (eidors.org) to simulate electrical stimulation and recording, respectively. Established models for myelinated and unmyelinated axons were adapted to the small‐diameter axons found in the pelvic nerve and implemented in NEURON (neuron.yale.edu), and parameter sensitivity was established using Sobel’ sensitivity analysis for different fascicle arrangements and orientations.ResultsThe pelvic nerve consists of mixed sensory and motor fascicles, with sensory projections to lower urinary or intestinal tracts projecting in distinct fascicles. Sensitivity profiles to extracellular stimulation depend on the size and orientation of the fascicles, as well as their axon type and diameter. Within‐fascicle selectivity is enhanced in the largest fascicles of the pelvic nerve, and overall thresholds are reduced in the smallest fascicles. The stimulus thresholds and conduction velocities of the small myelinated axons depend on the ultrastructural geometry of the nodal and internodal regions, with less dependence on the juxtanode, in an axon‐type‐dependent manner. Extracellular recording sensitivity profiles for clinically realistic electrodes were computed in EIDORS and validated in SIM4LIFE for predicting spontaneous and electrically evoked activity recordings. Extracellular recording sensitivity and stimulus thresholds were both most closely correlated with axon‐electrode distance.ConclusionThe macroscopic and microscopic structure of the pelvic nerve alters its sensitivity to electrical stimulation, as well as the selectivity of extracellular electrical recording. EIDORS can be used to accurately simulate extracellular recording in complex, heterogenous neural geometries.Support or Funding InformationNIH SPARC 3OT2OD023872‐01S4

The formation of paranodal spirals at the ends of CNS myelin sheaths requires the planar polarity protein Vangl2.

During axonal ensheathment, noncompact myelin channels formed at lateral edges of the myelinating process become arranged into tight paranodal spirals that resemble loops when cut in cross section. These adhere to the axon, concentrating voltage-dependent sodium channels at nodes of Ranvier and patterning the surrounding axon into distinct molecular domains. The signals responsible for forming and maintaining the complex structure of paranodal myelin are poorly understood. Here, we test the hypothesis that the planar cell polarity determinant Vangl2 organizes paranodal myelin. We show that Vangl2 is concentrated at paranodes and that, following conditional knockout of Vangl2 in oligodendrocytes, the paranodal spiral loosens, accompanied by disruption to the microtubule cytoskeleton and mislocalization of autotypic adhesion molecules between loops within the spiral. Adhesion of the spiral to the axon is unaffected. This results in disruptions to axonal patterning at nodes of Ranvier, paranodal axon diameter and conduction velocity. When taken together with our previous work showing that loss of the apico-basal polarity protein Scribble has the opposite phenotype-loss of axonal adhesion but no effect on loop-loop autotypic adhesion-our results identify a novel mechanism by which polarity proteins control the shape of nodes of Ranvier and regulate conduction in the CNS.

Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity.

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.

Estimating axon conduction velocity in vivo from microstructural MRI

The conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humans in vivo from non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are two major challenges that this paper aims to address: (1) Much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV that can be captured when predicting CV purely from parameters that have been reported to be estimatable from MRI: inner axon diameter (AD) and g-ratio. (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown. Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters. The investigations suggest that 85% of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by the previously reported model by Rushton. Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). For our equipment set-up and acquisition protocol, CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is high (above 4μm). CV estimates are robust to errors in g-ratio estimation but are highly sensitive to errors in AD estimation, particularly where ADs are small. We additionally show CV estimates in human corpus callosum in a small number of subjects. In conclusion, we demonstrate accurate CV estimates are possible in regions of the brain where AD is sufficiently large. Problems with estimating ADs for smaller axons presents a problem for estimating CV across the whole CNS and should be the focus of further study.

HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons.

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at the subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can be bidirectionally modulated by a HCN channel blocker, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mouse cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 µM; estimated endogenous cAMP concentration 13 µM). In addition, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily by altering the resting membrane potential and are associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators with an opportunity to finely tune energy consumption and temporal delays across axons in the brain.

Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity.

Myelination increases the conduction velocity in long‐range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement‐related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike‐time arrivals through long‐range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.