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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Book•
23 Jan 2013
7 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...neuropathies such as GBS and MMN [18] (see Figure 1)....
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...Severe focal demyelinations, internodal and paranodal, paranodal-internodal (IFD and PFD, PIFD) are specific indicators for acquired demyelinating neuropathies such as GBS and MMN [18] (see Figure 1)....
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...Mild systematic and severe focal demyelination correspond to hereditary (CMT1A) and acquired (CIDP, GBS and MMN) neuropathies (Table 1)....
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...for example, genetic factors seem to more strongly correlate to internodal disease processes and immunological dysfunctions cause paranodal abnormalities [18]....
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...Correspondence between types of demyelination and diseases according to Stephanova and Dimitrov [18]....
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TL;DR: The study summarizes the insights gained from these modeling investigations of the accommodative mechanisms underlying the threshold electrotonus abnormalities observed in demyelinating neuropathies such as Charcot-Marie-Tooth type 1A and chronic inflammatory demYelinating polyneuropathy.
6 citations
TL;DR: The study confirms that focal demyelinations are specific indicators for acquireddemyelinating neuropathies and excitability-based approaches that have shown strong potential as diagnostic tools in systematically demYelinated conditions may not be useful in detecting mild focal demi-yelination, independently of whether they are internodal, paranodals, or paranodalinternodal.
Abstract: Membrane properties such as potentials (intracellular, extracellular, electrotonic) and axonal excitability indices (strength–duration and charge–duration curves, strength–duration time constants, rheobasic currents, recovery cycles) can now be measured in healthy subjects and patients with demyelinating neuropathies. They are regarded here in two cases of simultaneously reduced paranodal seal resistance and myelin lamellae in one to three consecutive internodes of human motor nerve fiber. The investigations are performed for 70 and 96% myelin reduction values. The first value is not sufficient to develop a conduction block, but the second leads to a block and the corresponding demyelinations are regarded as mild and severe. For both the mild and severe demyelinations, the paranodally internodally focally demyelinated cases (termed as PIFD1, PIFD2, and PIFD3, respectively, with one, two, and three demyelinated internodes) are simulated using our previous double-cable model of the fiber. The axon model consists of 30 nodes and 29 internodes. The membrane property abnormalities obtained can be observed in vivo in patients with demyelinating forms of Guillain-Barre syndrome (GBS) and multifocal motor neuropathy (MMN). The study confirms that focal demyelinations are specific indicators for acquired demyelinating neuropathies. Moreover, the following changes have been calculated in our previous papers: (1) uniform reduction of myelin thickness in all internodes (Stephanova et al. in Clin Neurophysiol 116: 1153–1158, 2005); (2) demyelination of all paranodal regions (Stephanova and Daskalova in Clin Neurophysiol 116: 1159–1166, 2005a); (3) simultaneous reduction of myelin thickness and paranodal demyelination in all internodes (Stephanova and Daskalova in Clin Neurophysiol 116: 2334–2341, 2005b); and (4) reduction of myelin thickness of up to three internodes (Stephanova et al., in J Biol Phys, 2006a,b, DOI: 10.1007/s10867-005-9001-9; DOI: 10.1007/s10867-006-9008-x). The mem- brane property abnormalities obtained in the homogenously demyelinated cases are quite different and abnormally greater than those in the case investigated here of simultaneous reduction in myelin thickness and paranodal demyelination of up to three internodes. Our previous and present results show that unless focal demyelination is severe enough to cause outright conduction block, changes are so slight as to be essentially indistinguishable from normal values. Consequently, the excitability-based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations, independently of whether they are internodal, paranodal, or paranodal internodal.
6 citations
TL;DR: It is concluded that persistent reflection is a possible mechanism for ectopic activity in MS patients, being more prominent in higher temperatures and severe axonal demyelination.
Abstract: Ectopic activity in multiple sclerosis (MS) patients has been traditionally attributed to hyperexcitability of the demyelinated axon segments. Here, we propose that the same outcome may be the result of persistent reflection—the continuous reactivation of the axonal nodes that limit a demyelinated internodal segment. Using computer simulations, we studied the patterns of impulse propagation for a wide range of electrophysiological conditions. In uniformly myelinated fibers, increasing the temperature enabled successful propagation with no blocks in more severe conditions of demyelination. Secondary activations that were originated at the paranodes were formed for temperatures lower than T = 305 K, and at the condition of high sodium channel excitability. Non-sustained and persistent reflections appeared in the case of focally demyelinated fibers, and only within a narrow range of parameters of high temperature and membrane excitability. Persistent reflection reached steady state in ionic currents within 4 ms, and was characterized with a very high activation frequency of 1.504 ± 0.039 kHz. We conclude that persistent reflection is a possible mechanism for ectopic activity in MS patients, being more prominent in higher temperatures and severe axonal demyelination. Eliminating these symptoms may be addressed by cooling the body or by applying pharmacological agents to alter excitability properties.
6 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...Zlochiver [100] modeled persistent resonant reflection across a single focal demyelination plaque and found that this effect was sensitive to temperature and axon diameter....
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TL;DR: The study investigates the contributions of the aqueous layers within the myelin sheath on multiple membrane properties of simulated fibre demyelinations and provides new and important information on the mechanisms of chronic Demyelinating neuropathies, such as chronic inflammatory demyELinating polyneuropathy (CIDP).
Abstract: Recently, patients with chronic demyelinating neuropathies have demonstrated significant abnormalities in their multiple nerve excitability properties measured by a non-invasive threshold tracking technique. In order to expand our studies on the possible mechanisms underlying these abnormalities, which are not yet well understood, we investigate the contributions of the aqueous layers within the myelin sheath on multiple membrane properties of simulated fibre demyelinations. Four degrees of systematic paranodal demyelinations (two mild demyelinations termed PSD1 and PSD2, without/with aqueous layers respectively, and two severe demyelinations termed PSD3 and PSD4, with/without aqueous layers, respectively) are simulated using our previous multi-layered model of human motor nerve fibre. We studied the following parameters of myelinated axonal function: potentials (intracellular action, electrotonic — reflecting the propagating and accommodative fibre processes, respectively) and strength-duration time constants, rheobases, recovery cycles (reflecting the adaptive fibre processes). The results show that each excitability parameter is markedly potentiated when the aqueous layers within their paranodally demyelinated sheaths are taken into account. The effect of the aqueous layers is significantly higher on the propagating processes than on the accommodative and adaptive processes in the fibres. The aqueous layers restore the action potential propagation, which is initially blocked when they are not taken into account. The study provides new and important information on the mechanisms of chronic demyelinating neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP).
4 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...One of the most anatomically sophisticated models includes representation of the complex aqueous sheath structure of myelin lamellae as a series of interconnecting parallel lamellae in a model of motor nerves [30,80]....
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