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
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TL;DR: In this article, van Cholestear et al. describe how bier n e b e n regelrechter Verkn/ieherung in Form rhombisdier K~irnclten zwisebengelagert, l)iese vergr/isssrn sich and crsdlsinen dann in zu unregelmiissigen Itaufen zusammsngebacl~enen kr?~stallinisehen ziemlich grossen Kgrnern, an densn
Abstract: i/al[~erde wird bier n e b e n regelrechter Verkn/ieherung in Form rhombisdier K~irnclten zwisebengelagert, l)iese vergr/isssrn sich und crsdlsinen dann in zu unregelmiissigen Itaufen zusammsngebacl~enen kr?~stallinisehen ziemlich grossen Kgrnern, an densn man hin nnd wieder dis rhombische TaM noch wabrnet~msn kann. Van Cholestearintafsln dutch geringere Durchsichtigksit, wenigsr ansgebildete Form, grSssere Masse oder Dicks und anders Winkel deutlich verschieden, verwandein sieh diese kr~stallinischen ttaufen, ohne Entwicklung yon Kohlensiiure, bsim Zusatzs yon Schwefels~ure in schgns G~fpskrs, stalle; sis sind also wahrscheinlieh phospbsrsourer KMk, wie ouch die Vergleichung mit kiinstlich dargestelltem phosphorsauren Kalke zeigt.
116 citations
TL;DR: A network collapse of Delta psi(m) under criticality leads to: energetic failure, temporal and regional alterations in action potential (AP), development of zones of impaired conduction in the myocardium, and, ultimately, a fatal ventricular arrhythmia.
111 citations
"Physiological Dynamics in Demyelina..." refers background or methods in this paper
...There are many ways mitochondrial function can go awry and the compensatory pathways are equally complicated [53,60,61]....
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...Multi-scale models of heart, for example, have been used to link altered mitochrondrial Ca2+ signaling to arrhythmia [60]....
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TL;DR: A theoretical analysis of the passive electrical properties of normal myelinated nerve suggests that the function of the voltage-dependent potassium channels in theinternodal axolemma under the myelin sheath is to permit the generation of an internodal resting potential.
Abstract: A theoretical analysis of the passive electrical properties of normal myelinated nerve suggests that the function of the voltage-dependent potassium channels in the internodal axolemma under the myelin sheath is to permit the generation of an internodal resting potential. Calculation shows that if this internodal potential were not present, the nodal potential would be reduced (by electrotonic short-circuiting) thus impairing the security of conduction. This impairment is particularly pronounced with smaller diameter fibres.
105 citations
Journal Article•
TL;DR: : Lorcaserin (Belviq), an appetite suppressant; pertuzumab (Perjeta) for HER-2- positive metastatic breast cancer; MenHibrix vaccine for meningococcal infections and influenza; icosapent ethyl (Vascepa) for reducing triglycerides; and aclidinium inhalation (Tudorza) powder for bronchospasm in COPD.
Abstract: Mirabegron (Myrbetriq) for overactive bladder; phentermine/topiramate ER (Qsymia) for weight management; and ocriplasmin injection (Jetrea) for vitreomacular adhesion.
104 citations
TL;DR: The results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP, and Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membrane potential was normal and pathology was relatively minor.
Abstract: Guillain-Barre syndrome is classified into acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) by electrodiagnostic and pathological criteria. In AMAN, the immune attack appears directed against the axolemma and nodes of Ranvier. Threshold tracking was used to measure indices of axonal excitability (refractoriness, supernormality, and threshold electrotonus) for median nerve axons at the wrist of patients with AMAN (n = 10) and AIDP (n = 8). Refractoriness (the increase in threshold current during the relative refractory period) was greatly increased in AMAN patients, but the abruptness of the threshold increases at short interstimulus intervals indicated conduction failure distal to the stimulation (ie, an increased refractory period of transmission). During the 4 week period from onset, the high refractoriness returned toward normal, and the amplitude of the compound muscle action potential increased, consistent with improvement in the safety margin for impulse transmission in the distal nerve. In contrast, refractoriness was normal in AIDP, even though there was marked prolongation of distal latencies. Supernormality and threshold electrotonus were normal in both groups of patients, suggesting that, at the wrist, membrane potential was normal and pathology was relatively minor. These results support the view that the predominantly distal targets of immune attack are different for AMAN and AIDP. Possible mechanisms for the reduced safety factor in AMAN are discussed.
104 citations