Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling
07 Sep 2015-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 16, Iss: 9, pp 21215-21236
TL;DR: This work will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.
Abstract: Despite intense research, few treatments are available for most neurological disorders. Demyelinating diseases are no exception. This is perhaps not surprising considering the multifactorial nature of these diseases, which involve complex interactions between immune system cells, glia and neurons. In the case of multiple sclerosis, for example, there is no unanimity among researchers about the cause or even which system or cell type could be ground zero. This situation precludes the development and strategic application of mechanism-based therapies. We will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. By making testable predictions and revealing critical gaps in existing knowledge, such models can help direct research and will provide a rigorous framework in which to integrate new data as they are collected. Nowadays, there is no shortage of data; the challenge is to make sense of it all. In that respect, computational modeling is an invaluable tool that could, ultimately, transform how we understand, diagnose, and treat demyelinating diseases.
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TL;DR: The data showed that repeatability and comparability depend largely on the marker for the FVF (NODDI outperformed TFD), and that they were improved by masking, and that the calibration procedure is crucial, for example, calibration to a lower g‐ratio value than the commonly used one.
Abstract: A recent method, denoted in vivo g-ratio-weighted imaging, has related the microscopic g-ratio, only accessible by ex vivo histology, to noninvasive MRI markers for the fiber volume fraction (FVF) and myelin volume fraction (MVF). Different MRI markers have been proposed for g-ratio weighted imaging, leaving open the question which combination of imaging markers is optimal. To address this question, the repeatability and comparability of four g-ratio methods based on different combinations of, respectively, two imaging markers for FVF (tract-fiber density, TFD, and neurite orientation dispersion and density imaging, NODDI) and two imaging markers for MVF (magnetization transfer saturation rate, MT, and, from proton density maps, macromolecular tissue volume, MTV) were tested in a scan-rescan experiment in two groups. Moreover, it was tested how the repeatability and comparability were affected by two key processing steps, namely the masking of unreliable voxels (e.g., due to partial volume effects) at the group level and the calibration value used to link MRI markers to MVF (and FVF). Our data showed that repeatability and comparability depend largely on the marker for the FVF (NODDI outperformed TFD), and that they were improved by masking. Overall, the g-ratio method based on NODDI and MT showed the highest repeatability (90%) and lowest variability between groups (3.5%). Finally, our results indicate that the calibration procedure is crucial, for example, calibration to a lower g-ratio value (g = 0.6) than the commonly used one (g = 0.7) can change not only repeatability and comparability but also the reported dependency on the FVF imaging marker. Hum Brain Mapp 39:24-41, 2018. © 2017 Wiley Periodicals, Inc.
38 citations
Cites background from "Physiological Dynamics in Demyelina..."
...It has been suggested that in the healthy condition axons and their microscopic substructures (e.g., their g-ratio) are finely tuned biological devices and that changes of their composition can lead to clinical syndromes [Coggan et al., 2015]....
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..., their g-ratio) are finely tuned biological devices and that changes of their composition can lead to clinical syndromes [Coggan et al., 2015]....
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TL;DR: In this paper, the authors present a review of the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches.
38 citations
Posted Content•
TL;DR: A second review on the topic of g-ratio mapping using MRI with a summary of the most recent developments in the field providing methodological background is published.
Abstract: The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.
25 citations
Cites background from "Physiological Dynamics in Demyelina..."
...As the central nervous system appears to communicate at physical limits to constrain metabolic demands (Salami et al., 2003; Hartline and Colman, 2007; Coggan et al., 2015), small deviations from the optimal g-ratio value (0....
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TL;DR: Over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes, and mitochondrial damage, depleted energy level and decreased ATPase activities were observed in mice exposed to Fe2O3-NPs.
Abstract: Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.
15 citations
References
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TL;DR: The study summarizes the results from these modelling investigations on the mechanisms underlying the conduction slowing/block and accommodative processes in focal demyelinating neuropathies such as Guillain–Barré syndrome and multifocal motor neuropathy.
Abstract: To clarify the differences between the mechanisms of conduction slowing/block and accommodative processes in focal demyelinating neuropathies, this computational study presents the kinetics of the ionic, transaxonal and transmyelin currents defining the intracellular and electrotonic potentials in different segments of human motor nerve fibres. The computations use our previous double cable model of the fibres. The simulated fibres have focal demyelination of internodes, paranodes or both together. The intracellular potentials are defined mainly by the Na+ current, as the contribution of the K+ fast and K+ slow currents to the total nodal ionic current is negligible. The paranodal demyelinations cause an increase in the transaxonal current and a decrease in the transmyelin current at the paranodal segments. However, there is an inverse relationship between the transaxonal and transmyelin currents at the same segments in the cases of internodal demyelination. The internodal ionic channels beneath the myelin sheath do not contribute to the intracellular potentials, but they show a high sensitivity to long-lasting pulses. The slow components of the electrotonic potentials depend on the activation of the channel types in the nodal or internodal axolemma, whereas the fast components of the potentials are determined mainly by the passive cable responses. However, the current kinetics changes (defining the investigated electrotonic changes) are relatively weak. The study summarizes the results from these modelling investigations on the mechanisms underlying the conduction slowing/block and accommodative processes in focal demyelinating neuropathies such as Guillain–Barre syndrome and multifocal motor neuropathy.
4 citations
TL;DR: The present results suggest that the electrotonic potentials in patients with CIDP are in high risk for blocking not only during hypothermia and hyperthermia, but they are also in risk for worsening at the temperature range of 37-39°C.
Abstract: Threshold electrotonus changes have been studied following warming to 37°C and cooling to 25°C in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To extend the tracking of these changes also during hypothermia (≤ 25°C) and hyperthermia (≥ 40°C), and to explain their mechanisms, we investigate the effects of temperature (from 20°C to 42°C) on polarizing nodal and internodal electrotonic potentials and their current kinetics in previously simulated case of 70% CIDP. The computations use our temperature-dependent multi-layered model of the myelinated human motor nerve fiber. While the changes of electrotonic potentials and their current kinetics are largely similar for the physiological range of 28–37°C, they are altered during hypothermia and hyperthermia in the normal and CIDP cases. The normal (at 37°C) resting membrane potential is further depolarized or hyperpolarized during hypothermia or hyperthermia, respectively, and the internodal current types defining these changes are the same for both cases. Unexpectedly, our results show that in the CIDP case, the lowest and highest critical temperatures for blocking of electrotonic potentials are 20°C and 39°C, while in the normal case the highest critical temperature for blocking of these potentials is 42°C. In the temperature range of 20–39°C, the relevant potentials in the CIDP case, except for the lesser value (at 39°C) in hyperpolarized resting membrane potential, are modified: (i) polarizing nodal and depolarizing internodal electrotonic potentials and their defining currents are increased in magnitude; (ii) inward rectifier (IIR) and leakage (ILk) currents, defining the hyperpolarizing internodal electrotonic potential, are gradually increased with the rise of temperature from 20°C to 39°C, and (iii) the accommodation to long-lasting hyperpolarization is greater than to depolarization. The present results suggest that the electrotonic potentials in patients with CIDP are in high risk for blocking not only during hypothermia and hyperthermia, but they are also in risk for worsening at the temperature range of 37–39°C.
3 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...With their temperature-dependent version of the model of the myelinated human motor nerve fiber, Stephanova and Daskalova [105] showed that the electrotonic potentials in patients with CIDP are in high risk for blocking during hypo- and even mild hyperthermia and suggest mechanisms involving increased magnitude of polarizing nodal and depolarizing internodal electrotonic potentials, inward rectifier K+ and leak K+ currents increase with temperature, and the accommodation to long-lasting hyperpolarization is greater than to depolarization....
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01 Jan 2014
TL;DR: One approach involves incorporating known or suspected ion channel changes into normal axon models to test whether such changes can explain pathological changes in excitability and then working backward to identify which ionChannel changes may be involved.
Abstract: Reversing pathological changes in nerve excitability is an important clinical goal. Achieving that goal requires identification of the underlying molecular changes and a clear understanding of how excitability is altered on the basis of those changes. Computational modeling plays an important role in addressing those issues. One approach involves incorporating known or suspected ion channel changes into normal axon models to test whether such changes can explain pathological changes in excitability. An alternative approach involves reproducing the pathological changes in excitability and then working backward to identify which ion channel changes may be involved.
1 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...axonal dysfunction especially when combined with experimental results that might better pinpoint mechanisms [96]....
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