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.

Axon Diameter Measurements using Diffusion MRI are Infeasible

The feasibility of non-invasive axonal diameter quantification with diffusion MRI is a strongly debated topic due to the neuroscientific potential of such information and its relevance for the axonal signal transmission speed. It has been shown that under ideal conditions, the minimal diameter producing detectable signal decay is bigger than most human axons in the brain, even using the strongest currently available MRI systems. We show that resolving the simplest situations including multiple diameters is unfeasible even with diameters much bigger than the diameter limit. Additionally, the recently proposed effective diameter resulting from fitting a single value over a distribution is almost exclusively influenced by the biggest axons. We show how impractical this metric is for comparing different distributions. Overall, axon diameters currently cannot be quantified by diffusion MRI in any relevant way.

No Association Between Structural Properties of Corpus Callosum and Handedness: Evidence from the Constrained Spherical Deconvolution Approach

Handedness is the most prominent trait of functional asymmetry in humans, associated with lateralized cognitive functions and considered in relation to mental disorders. However, the neuroanatomical correlates of handedness are still unclear. It has been hypothesized that the structural properties of sub-regions of the corpus callosum (CC) are linked to handedness. Nevertheless, tractography studies of the relation between directly measured structural properties of CC subregions and handedness are lacking. The Constrained Spherical Deconvolution (CSD) approach enables full reconstruction of the sub-regions of the CC. The current study aimed to investigate the relation between the structural properties of the CC, such as volume and the CSD metric, referred to as hindrance modulated orientational anisotropy (HMOA), and handedness. Handedness was considered in two dimensions: direction (right-handed, ambidextrous, left-handed) and degree (the absolute values of Handedness quotient). We found no association between 1) volume or HMOA as a proxy of microstructural properties, namely the axonal diameter and fiber dispersion, of each sub-region and 2) either the direction or the degree of handedness. These findings suggest the absence of a direct relation between sub-regions of the CC and handedness, demonstrating the necessity of future tractography studies.

Wrapping glia regulates neuronal signaling speed and precision in the peripheral nervous system of Drosophila

The functionality of the nervous system requires transmission of information along axons with high speed and precision. Conductance velocity depends on axonal diameter whereas signaling precision requires a block of electrical crosstalk between axons, known as ephaptic coupling. Here, we use the peripheral nervous system of Drosophila larvae to determine how glia regulates axonal properties. We show that wrapping glial differentiation depends on gap junctions and FGF-signaling. Abnormal glial differentiation affects axonal diameter and conductance velocity and causes mild behavioral phenotypes that can be rescued by a sphingosine-rich diet. Ablation of wrapping glia does not further impair axonal diameter and conductance velocity but causes a prominent locomotion phenotype that cannot be rescued by sphingosine. Moreover, optogenetically evoked locomotor patterns do not depend on conductance speed but require the presence of wrapping glial processes. In conclusion, our data indicate that wrapping glia modulates both speed and precision of neuronal signaling.

Actomyosin Contractility in the Generation and Plasticity of Axons and Dendritic Spines

Actin and non-muscle myosins have long been known to play important roles in growth cone steering and neurite outgrowth. More recently, novel functions for non-muscle myosin have been described in axons and dendritic spines. Consequently, possible roles of actomyosin contraction in organizing and maintaining structural properties of dendritic spines, the size and location of axon initial segment and axonal diameter are emerging research topics. In this review, we aim to summarize recent findings involving myosin localization and function in these compartments and to discuss possible roles for actomyosin in their function and the signaling pathways that control them.

4362 The Utilization of Polyethylene Glycol Fusion to Improve Facial Reanimation

OBJECTIVES/GOALS: This study’s goal is to determine whether intraoperative treatment of facial nerves with polyethylene glycol (PEG) fusion technology improves facial paralysis outcomes. Improved facial nerve regeneration in facial paralysis patients would lead to improved recovery time and effectiveness. METHODS/STUDY POPULATION: 30 rats were utilized; 15 underwent facial nerve regeneration without PEG fusion, and 15 with PEG fusion. Facial paralysis was initiated on the left by transection of the buccal and marginal mandibular branches of facial nerve. The buccal branch was repaired though microsuture technique. Neurorrhaphy sites of rats in the PEG group were exposed to calcium free saline, methylene blue, and polyethylene glycol. Nerve continuity was assessed post-operative in 5 animals in each group through electron microscopy. Functionality was assessed in the other 10 per group by EMG and whisker analysis after surgery, and weekly for 8 weeks. At 8 weeks, nerves and distal muscles were histologically analyzed. RESULTS/ANTICIPATED RESULTS: PEG fusion technology immediately restored axonal continuity following surgery, demonstrated by electron microscopy. Electrophysiology was also similarly restored across the site immediately, determined through intraoperative nerve stimulation, in the PEG fusion group. The nonintervention group showed dramatically reduced functional recovery than the PEG fusion group following surgery, shown by lower whisking activity and poor electrophysiology outcomes. Furthermore, the PEG fusion group showed statistically significant higher fascicle counts, myelination diameter, axonal diameter, and distal muscle fibers histologically. DISCUSSION/SIGNIFICANCE OF IMPACT: This study demonstrates that polyethylene fusion technology may improve facial reanimation outcomes. PEG is already a FDA-approved drug, and thus the pathway to translational clinical application of this work may thus be streamlined, bringing new options to patients with facial paralysis.

Multimodal principal component analysis to identify major features of white matter structure and links to reading

ABSTRACTThe role of white matter fibers in reading has been established by diffusion tensor imaging (DTI), but DTI cannot identify specific microstructural features driving these relationships. Neurite orientation dispersion and density imaging (NODDI), inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT) can be used to link more specific aspects of white matter microstructure and reading due to their sensitivity to axonal packing and fiber coherence (NODDI) and myelin (ihMT and mcDESPOT). We applied principal component analysis (PCA) to combine DTI, NODDI, ihMT and mcDESPOT measures (10 in total), identify major features of white matter structure, and link these features to both reading and age. Analysis was performed for nine reading-related tracts in 46 neurotypical 6-16 year olds. We identified three principal components (PCs) which explained 79.5% of variance in our dataset. PC1 probed tissue complexity, PC2 described myelin and axonal packing, while PC3 was related to axonal diameter. Mixed effects models regressions did not identify any relationships between principal components and reading skill. Further Bayes factor analysis revealed that absence of relationships was not due to low power. PC1 suggested increases in tissue complexity with age in the left arcuate fasciculus, while PC2 suggested increases in myelin and axonal packing with age in the bilateral arcuate, inferior longitudinal, inferior fronto-occipital fasciculi, and splenium. Multimodal white matter imaging and PCA produce microstructurally informative, powerful principal components which can be used by future studies of development and cognition.

The membrane periodic skeleton is an actomyosin network that regulates axonal diameter and conduction

Neurons have a membrane periodic skeleton (MPS) composed of actin rings interconnected by spectrin. Here, combining chemical and genetic gain- and loss-of-function assays, we show that in rat hippocampal neurons the MPS is an actomyosin network that controls axonal expansion and contraction. Using super-resolution microscopy, we analyzed the localization of axonal non-muscle myosin II (NMII). We show that active NMII light chains are colocalized with actin rings and organized in a circular periodic manner throughout the axon shaft. In contrast, NMII heavy chains are mostly positioned along the longitudinal axonal axis, being able to crosslink adjacent rings. NMII filaments can play contractile or scaffolding roles determined by their position relative to actin rings and activation state. We also show that MPS destabilization through NMII inactivation affects axonal electrophysiology, increasing action potential conduction velocity. In summary, our findings open new perspectives on axon diameter regulation, with important implications in neuronal biology.