Browsing by Subject "Peripheral nerve"
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Item Characterization of the Electrical Properties of Mammalian Peripheral Nerve Laminae(Wiley, 2023) Horn, M. Ryne; Vetter, Christian; Bashirullah, Rizwan; Carr, Mike; Yoshida, Ken; Biomedical Engineering, School of Engineering and TechnologyBackground and objective: The intrinsic electrical material properties of the laminar components of the mammalian peripheral nerve bundle are important parameters necessary for the accurate simulation of the electrical interaction between nerve fibers and neural interfaces. Improvements in the accuracy of these parameters improve the realism of the simulation and enables realistic screening of novel devices used for extracellular recording and stimulation of mammalian peripheral nerves. This work aims to characterize these properties for mammalian peripheral nerves to build upon the resistive parameter set established by Weerasuriya et al. in 1984 for amphibian somatic peripheral nerves (frog sciatic nerve) that is currently used ubiquitously in the in-silico peripheral nerve modeling community. Methods: A custom designed characterization chamber was implemented and used to measure the radial and longitudinal impedance between 10 mHz and 50 kHz of freshly excised canine vagus nerves using four-point impedance spectroscopy. The impedance spectra were parametrically fitted to an equivalent circuit model to decompose and estimate the components of the various laminae. Histological sections of the electrically characterized nerves were then made to quantify the geometry and laminae thicknesses of the perineurium and epineurium. These measured values were then used to calculate the estimated intrinsic electrical properties, resistivity and permittivity, from the decomposed resistances and reactances. Finally, the estimated intrinsic electrical properties were used in a finite element method (FEM) model of the nerve characterization setup to evaluate the realism of the model. Results: The geometric measurements were as follows: nerve bundle (1.6 ± 0.6 mm), major nerve fascicle diameter (1.3 ± 0.23 mm), and perineurium thickness (13.8 ± 2.1 μm). The longitudinal resistivity of the endoneurium was estimated to be 0.97 ± 0.05 Ωm. The relative permittivity and resistivity of the perineurium were estimated to be 2018 ± 391 and 3.75 kΩm ± 981 Ωm, respectively. The relative permittivity and resistivity of the epineurium were found to be 9.4 × 106 ± 8.2 × 106 and 55.0 ± 24.4 Ωm, respectively. The root mean squared (RMS) error of the experimentally obtained values when used in the equivalent circuit model to determine goodness of fit against the measured impedance spectra was found to be 13.0 ± 10.7 Ω, 2.4° ± 1.3°. The corner frequency of the perineurium and epineurium were found to be 2.6 ± 1.0 kHz and 368.5 ± 761.9 Hz, respectively. A comparison between the FEM model in-silico impedance experiment against the ex-vivo methods had a RMS error of 159.0 ± 95.4 Ω, 20.7° ± 9.8°. Conclusion: Although the resistive values measured in the mammalian nerve are similar to those of the amphibian model, the relative permittivity of the laminae bring new information about the reactance and the corner frequency (frequency at peak reactance) of the peripheral nerve. The measured and estimated corner frequency are well within the range of most bioelectric signals, and are important to take into account when modeling the nerve and neural interfaces.Item Chronic kidney disease and peripheral nerve function in the Health, Aging and Body Composition Study(Oxford University Press, 2019-04) Moorthi, Ranjani N.; Doshi, Simit; Fried, Linda F.; Moe, Sharon M.; Sarnak, Mark J.; Satterfield, Suzanne; Schwartz, Ann V.; Shlipak, Michael; Lange-Maia, Brittney S.; Harris, Tamara B.; Newman, Anne B.; Strotmeyer, Elsa S.; Medicine, School of MedicineBACKGROUND: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. METHODS: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999-2000) and nerve function measurements at Year 4 (2000-01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. RESULTS: Participants with CKD (n = 476) were older (77 ± 3 versus 75 ± 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1-2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1-1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1-2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1-2.0)]. CONCLUSIONS: CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes.Item DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses(Elsevier, 2024) Asghari Adib, Elham; Shadrach, Jennifer L.; Reilly-Jankowiak, Lauren; Dwivedi, Manish K.; Rogers, Abigail E.; Shahzad, Shameena; Passino, Ryan; Giger, Roman J.; Pierchala, Brian A.; Collins, Catherine A.; Anatomy, Cell Biology and Physiology, School of MedicineAxotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.Item Heregulin Activity Assays for Residual Testing of Cell Therapy Products(BMC, 2021-11-12) Monje, Paula V.; Bacallao, Ketty; Aparicio, Gabriela I.; Lalwani, Anil; Neurological Surgery, School of MedicineBackground: Heregulin is a ligand for the protooncogene product ErbB/HER that acts as a key mitogenic factor for human Schwann cells (hSCs). Heregulin is required for sustained hSC growth in vitro but must be thoroughly removed before cell collection for transplantation due to potential safety concerns. The goal of this study was to develop simple cell-based assays to assess the effectiveness of heregulin addition to and removal from aliquots of hSC culture medium. These bioassays were based on the capacity of a β1-heregulin peptide to elicit ErbB/HER receptor signaling in adherent ErbB2+/ErbB3+ cells. Results: Western blotting was used to measure the activity of three different β1-heregulin/ErbB-activated kinases (ErbB3/HER3, ERK/MAPK and Akt/PKB) using phospho-specific antibodies against key activating residues. The duration, dose-dependency and specificity of β1-heregulin-initiated kinase phosphorylation were investigated, and controls were implemented for assay optimization and reproducibility to detect β1-heregulin activity in the nanomolar range. Results from these assays showed that the culture medium from transplantable hSCs elicited no detectable activation of the aforementioned kinases in independent rounds of testing, indicating that the implemented measures can ensure that the final hSC product is devoid of bioactive β1-heregulin molecules prior to transplantation. Conclusions: These assays may be valuable to detect impurities such as undefined soluble factors or factors for which other biochemical or biological assays are not yet available. Our workflow can be modified as necessary to determine the presence of ErbB/HER, ERK, and Akt activators other than β1-heregulin using native samples, such as fresh isolates from cell- or tissue extracts in addition to culture medium.Item Interaction between Schwann cells and other cells during repair of peripheral nerve injury(Wolters Kluwer, 2021-01) Qu, Wen-Rui; Zhu, Zhe; Liu, Jun; Song, De-Biao; Tian, Heng; Chen, Bing-Peng; Li, Rui; Deng, Ling-Xiao; Neurological Surgery, School of MedicinePeripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.Item Optical tissue clearing enables rapid, precise and comprehensive assessment of three-dimensional morphology in experimental nerve regeneration research(Wolters Kluwer, 2022) Daeschler, Simeon C.; Zhang, Jennifer; Gordon, Tessa; Borschel, Gregory H.; Surgery, School of MedicineMorphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children's Laboratory Animal Services Committee (49871/9) on November 9, 2019.Item Risk Factors for a False-Negative Examination in Complete Upper Extremity Nerve Lacerations(Sage, 2021) Loewenstein, Scott N.; Wulbrecht, Reed; Leonhard, Vanessa; Sasor, Sarah; Cook, Julia; Timsina, Lava; Adkinson, Joshua; Surgery, School of MedicineBackground: Many patients with complete nerve lacerations after upper extremity trauma have a documented normal peripheral nerve examination at the time of initial evaluation. The purpose of this study was to determine whether physician-, patient-, and injury-related factors increase the risk of false-negative nerve examinations. Methods: A statewide health information exchange was used to identify complete upper extremity nerve lacerations subsequently confirmed by surgical exploration at 1 pediatric and 2 adult level I trauma centers in a single city from January 2013 to January 2017. Charts were manually reviewed to build a database that included Glasgow Coma Scale score, urine drug screen results, blood alcohol level, presence of concomitant trauma, type of injury, level of injury, laterality, initial provider examination, and initial specialist examination. Bivariate and multivariable analyses were performed to evaluate risk factors for a false-negative examination. Results: Two hundred eighty-eight patients met inclusion criteria. The overall false-negative examination rate was 32.5% at initial encounter, which was higher among emergency medicine physicians compared with extremity subspecialists (P < .001) and among trauma surgeons compared with surgical subspecialists (P = .002). The false-negative rate decreased to 8% at subsequent encounter (P < .001). Risk factors for a false-negative nerve examination included physician specialty, a gunshot wound mechanism of injury, injury at the elbow, and age greater than 71 years. Conclusion: There is a high false-negative rate among upper extremity neurotmesis injuries. Patients with an injury pattern that may lead to nerve injury warrant prompt referral to an upper extremity specialist in an effort to optimize outcomes.Item Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury(Elsevier, 2015-09-04) Deng, Ling-Xiao; Walker, Chandler; Xu, Xiao-Ming; Department of Anatomy & Cell Biology, IU School of MedicineAfter spinal cord injury (SCI), poor ability of damaged axons of the central nervous system (CNS) to regenerate causes very limited functional recovery. Schwann cells (SCs) have been widely explored as promising donors for transplantation to promote axonal regeneration in the CNS including the spinal cord. Compared with other CNS axonal pathways, injured propriospinal tracts display the strongest regenerative response to SC transplantation. Even without providing additional neurotrophic factors, propriospinal axons can grow into the SC environment which is rarely seen in supraspinal tracts. Propriospinal tract has been found to respond to several important neurotrophic factors secreted by SCs. Therefore, the SC is considered to be one of the most promising candidates for cell-based therapies for SCI. Since many reviews have already appeared on topics of SC transplantation in SCI repair, this review will focus particularly on the rationale of SC transplantation in mediating descending propriospinal axonal regeneration as well as optimizing such regeneration by using different combinatorial strategies. This article is part of a Special Issue entitled SI: Spinal cord injury.Item Using a Transection Paradigm to Enhance the Repair Mechanisms of an Investigational Human Cell Therapy(Sage, 2022) Chau, Monica J.; Quintero, Jorge E.; Monje, Paula V.; Voss, Stephen Randal; Welleford, Andrew S.; Gerhardt, Greg A.; van Horne, Craig G.; Neurological Surgery, School of MedicineOne promising strategy in cell therapies for Parkinson's disease (PD) is to harness a patient's own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD. Our group has pioneered the transplantation of transection-activated sural nerve fascicles into the brain of human subjects with PD. Our experience in sural nerve transplantation has supported the safety and feasibility of this approach. As part of a paradigm to assess the reparative properties of human sural nerve following a transection injury, we collected nerve tissue approximately 2 weeks after sural nerve transection for immunoassays from 15 participants, and collected samples from two additional participants for single nuclei RNA sequencing. We quantified the expression of key neuroprotective and select anti-apoptotic genes along with their corresponding protein levels using immunoassays. The single nuclei data clustered into 10 distinctive groups defined on the basis of previously published cell type-specific genes. Transection-induced reparative peripheral nerve tissue showed RNA expression of neuroprotective factors and anti-apoptotic factors across multiple cell types after nerve injury induction. Key proteins of interest (BDNF, GDNF, beta-NGF, PDGFB, and VEGF) were upregulated in reparative tissue. These results provide insight on this repair tissue's utility as a neuroprotective cell therapy.