TARGET AUDIENCE MRI specialists, bioengineers, physicists, mathematicians, physiologists, neuroradiologists, neurologists, cardiologists, physicians in general. OUTCOME/OBJECTIVES Attendees are expected to (i) appreciate the significance of the role of fluids in human physiology and pathology (ii) to approach physiology and disease in a holistic manner by considering the interacting dynamics of all relevant body fluid compartments. PURPOSE The problem I will address is the role of body fluid compartments and their dynamic interaction in the physiology and pathology of the Central Nervous System (CNS). The study started in 2010 and arose from scientific reports on cerebral venous outflow anomalies (intracranial and extracranial) and their potential role in disturbing CNS fluid physiology in the context of intracranial hypertension [1] and multiples sclerosis [2]. There have been more recent communications on the subject that include other diseases, notably Parkinson’s disease [3] and Meniere’s disease [4]. METHODS The problem has been studied (i) by first constructing a global anatomical picture of all major body fluid compartments, their connections and their interactions; (ii) through the use of MRI measurements and imaging aimed at identifying subjects with disorders in fluid compartments physiology; (iii) by constructing a full-body, global mathematical model for the fluid dynamics that includes heart, pulmonary circulation, respiration, arterial tree, miscrovasculature, venous tree, brain parenchyma and cerebrospinal fluid; (iv) by implementing numerical algorithms to solve the equations on a computer and produce theoretical subject-specific predictions ; (v) by validating numerical predictions against MRI measurements and published and (vi) by using the mathematical model to study specific conditions of interest. See [5], [6], [7]. RESULTS Computational studies of several pathologies of interest have quantitatively confirmed what was intuitively expected: alterations of the dynamics of one fluid compartment results in disturbances of the remaining ones. For example, cerebral venous outflow anomalies, intracranial or extracranial, result in disturbed CNS fluid physiology characterized by increased intracranial pressure, reverse flow, altered shear stresses, altered fluid transport, altered perfusion. See [8], [9], [10], [11]. These results have been confirmed by MRI measurements on patients with Idiopathic Intracranial Hypertension [12]. DISCUSSION The computational results on specific subjects with a specific condition partially begin to explain a complex chain of events that starts by associating fluid dynamics pathologies with specific diseases. CONCLUSION The first conclusion has an immediate clinical value and arises from considering all major fluid compartments in a holistic view [12]; this can be put in practice through MRI techniques, not just through mathematical modeling. Our paradigm also points the way to future research that could include the construction of even more complex models incorporating more processes and phenomena of interest. Examples are transport of solutes in the full body and more refined models of fluid compartments, including for instance, the peripheral lymphatic system, the (CNS) glympatic system and the newly discovered meningeal lymphatic system. Some progress has been made in this direction [13], [14]. A challenging largely unresolved issue is that of parameters, eg mechanical, geometrical, physiological. See [15], [16]. In close collaboration with MRI specialists, the mathematical model, can be an effective tool for testing medical hypotheses.

Acknowledgements

No acknowledgement found.

References

[1] N. Alperin, S. H. Lee, M. Mazda, S. G. Hushek, B. Roitberg, J. Goddwin, and T. Lichtor. Evidence for the importance of extracranial venous flow in patients with idiopathic intracranial hypertension (IIH). Acta Neurochir (2005) [Suppl] 95: 129–132. Springer-Verlag 2005. [2] P Zamboni, R Galeotti, E Menegatti, A M Malagoni, G Tacconi, S Dall’Ara, I Bartolomei, F Salvi. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399. doi:10.1136/jnnp.2008.157164. [3] Manju Liu, Haibo Xu, Yuhui Wang, Yi Zhong, Shuang Xia, David Utriainen, Tao Wang, and E. Mark Haacke. Patterns of Chronic Venous Insufficiency in the Dural Sinuses and Extracranial Draining Veins and Their Relationship with White Matter Hyperintensities for Patients with Parkinson's Disease.J Vasc Surg. 2015 June ; 61(6): 1511–1520.e1. doi:10.1016/j.jvs.2014.02.021. [4] A Bruno, L Califano, D Mastrangelo, M De Vizia, B Bernardo, F Salafia. Chronic cerebrospinal venous insufficiency in Ménière’s disease: diagnosis and treatment. Veins and Lymphatics 2014; volume 3:3854 [5] E F Toro and A Siviglia. Flow in collapsible tubes with discontinuous mechanical properties: mathematical model and exact solutions. Communications in Computational Physics. Vol. 13, Number 2, pp 361-385, Feb. 2013. [6] L O. Müller and E F. Toro. A global multi-scale model for the human circulation with emphasis on the venous system. International Journal for Numerical Methods in Biomedical Engineering. Volume 30, Issue 7, pages 681-725, July 2014. [7] L O Müller and E F. Toro. Enhanced global mathematical model for studying cerebral venous blood flow. Journal of Biomechanics. Volume 47, Issue 13, 17 October 2014,Pages 3361-3372. [8] L. O. Müller, E. F. Toro, E. M. Haacke and D. Utriainen. Impact of CCSVI on cerebral haemodynamics: a mathematical study using MRI angiographic and flow data. Phlebology, Vol. 31, No 5, pp 305-324, 2016, doi: 10.1177/0268355515586526. [9] E F. Toro, L O Müller, M Cristini, E Menegatti and P Zamboni. Impact of Jugular Vein Valve Function on Cerebral Venous Haemodynamics. Current Neurovascular Research. Vol. 12, No. 4, pages 384-397, 2015. DOI: 10.2174/1567202612666150807112357 [10] E F. Toro. Brain Venous Haemodynamics, Neurological Diseases and Mathematical Modelling. A Review. Applied Mathematics and Computation. Vol. 272, pp 542-579, 2016. doi:10.1016/j.amc.2015.06.066 [11] E F Toro, F Borgioli, Q Zhang, C Contarino, L O Müller and A Bruno. Inner-ear circulation in humans is disrupted by extracranial venous outow strictures: implications for Meniere's disease. Veins and Lymphatics. Volume 7:7156, 2018. [12] N Agarwal, C Contarino, L Bertazzi, N Limbucci, G Rossi and E F Toro. Intracranial dynamics changes in idiopathic intracranial hypertension: pre and post lumbar puncture, medical and stent placement. Current Neurovascular Research. Vol. 15, pp 1-9, 2018. [13] C Contarino and E F Toro. A one-dimensional mathematical model of collecting lymphatics coupled with an electro-uid-mechanical contraction model and valve dynamics Biomechanics and Modelling Mechanobiology. Published on line, July 2018.https://doi.org/10.1007/s10237-018-1050-7 [14] E F Toro, Q Zhang, B Thornber, A Scoz and C Contarino. A computational model for the dynamics of cerebrospinal fluid in the spinal subarachnoid space. ASME Journal of Biomechanical Engineering. Vol. 141(1). January 2019, doi: 10.1115/1.4041551. [15] A Caiazzo, F Caforio, G I Montecinos, L O Müller, P J Blanco and E F Toro. Assessment of unscented reduced-order Kalman filter for parameter identification in one-dimensional blood flow models using experimental data. International Journal for Numerical Methods in Biomedical Engineering. 2017; e2843; DOI 10.1002/cnm.2843 [16] M Petrella, S A Tokareva and E F Toro. Uncertainty Quantification Methodology for Hyperbolic Systems with Application to Blood Flow in Arteries. Journal of Computational Physics. Available online 1 March 2019.