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: It was deduced that the inward rectification is a property of the internodal axon, that the slow outward rectifier is present at the nodes, and probably the internodes as well, and that the 4AP‐sensitive channels have a minor nodal and a majorInternodal representation.
Abstract: 1. The nature, distribution and function of rectifying channels in rat spinal root myelinated axons has been assessed with selective blocking agents and a variety of intracellular and extracellular recording techniques. 2. The electrotonic responses of roots poisoned with tetrodotoxin (TTX) to constant current pulses had fast (rise time much less than 1 ms) and slow components, which were interpreted in terms of Barrett & Barrett's (1982) revised cable model for myelinated nerve. Depolarization evoked a rapid outward rectification (time constant, tau approximately 0.5 ms), selectively blocked by 4-aminopyridine (4AP, 1 mM), and a slow outward rectification (tau approximately 15 ms), selectively blocked by tetraethylammonium (TEA, 1 mM) or Ba2+ (0.5 mM). Hyperpolarization evoked an even slower inward rectification, selectively blocked by Cs+ (3 mM) but not by Ba2+. 3. From the different effects of the blocking agents on the fast and slow components of electrotonus, it was deduced (a) that the inward rectification is a property of the internodal axon, (b) that the slow outward rectifier is present at the nodes, and probably the internodes as well, and (c) that the 4AP-sensitive channels have a minor nodal and a major internodal representation. 4. TEA and Ba2+ reduced the accommodation of roots and fibres not poisoned with TTX to long current pulses, whereas 4AP facilitated short bursts of impulses in response to a single brief stimulus. 5. TEA and Ba2+ also abolished a late hyperpolarizing after-potential (peaking at 20-80 ms), while 4AP enhanced the depolarizing after-potential in normal fibres, and abolished an early hyperpolarizing after-potential (peaking at 1-3 ms) in depolarized fibres. Corresponding to the later after-potentials were post-spike changes in excitability and conduction velocity, which were affected similarly by the blocking agents. Cs+ increased the post-tetanic depression attributable to electrogenic hyperpolarization. 6. The physiological roles of the three different rectifying conductances are discussed. It is also argued that the prominent ohmic 'leak conductance', usually ascribed to the nodal axon, must arise in an extracellular pathway in series with the rectifying internodal axon.
341 citations
TL;DR: The pathological features of these central nervous system inflammatory demyelinating disorders are reviewed and neuropathological studies that have yielded novel insights into potential mechanisms involved in the formation of the demYelinated lesion are discussed.
Abstract: There has been significant progress in our understanding of the pathology and pathogenesis of central nervous system inflammatory demyelinating diseases. Neuropathological studies have provided fundamental new insights into the pathogenesis of these disorders and have led to major advances in our understanding of multiple sclerosis (MS) heterogeneity, the substrate of irreversible progressive disability in MS, the relationship between inflammation and neurodegeneration in MS, the neuroimaging correlates of MS lesions, and the pathogenesis of other central nervous system inflammatory disorders, including neuromyelitis optica, acute disseminated encephalomyelitis, and Balo's concentric sclerosis. Herein, we review the pathological features of these central nervous system inflammatory demyelinating disorders and discuss neuropathological studies that have yielded novel insights into potential mechanisms involved in the formation of the demyelinated lesion.
301 citations
Book•
01 Jan 1995
TL;DR: This book provides a comprehensive and up to date compendium that brings together contributions on the structure, function and pathophysiology of axons in both the peripheral and central nervous systems.
Abstract: This book provides a comprehensive and up to date compendium that brings together contributions on the structure, function and pathophysiology of axons in both the peripheral and central nervous systems. Authoritative and superbly illustrated, the 33 chapters and introduction have been authored by 49 world-renowned authorities. New areas, such as the molecular biology of ion channels and of myelination, the role of calcium in pathophysiology and regeneration, cell adhesion molecules and their roles in axo-glial interactions and axonal guidance, and optical recording methods, are highlighted. A generously referenced book which will provide essential reference to those working in this field.
271 citations
TL;DR: Dimensional analysis shows that these anatomical conditions are equivalent to Rushton's (1951) assumption of corresponding states, and conduction velocity will be proportional to fiber diameter, in complete agreement with the experimental findings.
263 citations
"Physiological Dynamics in Demyelina..." refers methods in this paper
...Goldman & Albus [66] modified this model to include a description of the nodal membrane derived from experimental data on Xenopus laevis myelinated nerve fibers as determined by Frankenhaeuser & Huxley [67]....
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...Goldman & Albus [66] modified this model to include a description of...
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TL;DR: The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal‐appearing white matter (NAWM) in multiple sclerosis brains.
Abstract: Objective:
The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains.
Methods:
Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels.
Results:
Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II+ microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity.
Interpretation:
The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities. ANN NEUROL 2011
253 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...In chronic active plaques, axonal loss of 20%–80% is apparent within peri-plaque white matter and normal distant white matter [45]....
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