1. Modeling Steady State Intracranial Pressures in Microgravity Scott A Stevens, PhD Penn State Erie William D Lakin, PhD The University of Vermont Paul L Penar, MD The University of Vermont

2. Motivation Many astronauts experience symptoms of Space Adaptation Sickness during the first few hours or days of spaceflight. The cause of all symptoms is not well understood. We are investigating possible causes via mathematical modeling. Are some symptoms of SAS caused by elevated intracranial pressure (ICP)?

3. Your Brain

4. Cerebrospinal Fluid (CSF)

5. A diagram of the lumped-parameter model

6. Assumption 1: Fluid flow is driven by pressure

7. Example: Flow from the capillaries to the veins

8. Filtration across the blood-brain barrier (BBB) The Starling Landis Equation:

9. = Hydrostatic pressure difference = Filtration across the blood-brain barrier = Filtration Coefficient = Reflection Coefficient = Colloid osmotic pressure difference

10. Colloid Osmotic Pressure

11. Volume changes are accommodated via compliance terms

12. Assumption 2: Volume changes are proportional to pressure difference changes

13. Example:

14. Conservation of Mass - Focus on Compartments I,C,S,F,T,B

15. Example: Ventricular CSF Compartment (F) Rate of Volume Change = flow in – flow out

16. Doing this in each compartment yields: where

17. The resulting system; has a unique steady state P* defined by and all solutions tend to P*.

18. 1.Intracranial pressures (P F and P B ) change in parallel with the changes in central venous pressure (P V ). 2.Intracranial pressures increase 0.37 mmHg for every one mmHg decrease in blood colloid osmotic pressure. Results

19. 1.Microgravity probably does not initiate intracranial hypertension. 2.The intracranial pressure (ICP) in microgravity may be less than that experienced lying down on earth. 3.The sickness associated with microgravity is probably not due to intracranial hypertension unless microgravity alters additional physiology. Conclusions:

20. Possible Causes: Consider possible alterations in the blood-brain barrier (BBB) in space. The lack of orthostatic pressure in microgravity. Radiation effects above low earth orbit

21. Capillary Membrane on Earth: Tight Proposed Capillary Membrane in Space: Leaky

22. Radiation effects on the BBB Leszczynski et al [1,2] (2002, 2004) - Cell phone radiation levels caused increases in the protein expression of hsp27 and p38MAPK in human endothelial cells. - It is hypothesized [1] that activation of hsp27 may cause an increase in blood-brain barrier permeability. Radiation exposure in space appears capable of adversely impacting the integrity of the blood-brain barrier.

23. A “leaky” blood-brain barrier is modeled in Q CB by either An increase in the filtration coefficient or A decrease in the reflection coefficient

24. With Normal BBB More leaky 6.3 mmHg drop in blood colloid osmotic pressure No change in central venous pressure

25. Conclusions If there is no alteration in the blood-brain barrier, it seems unlikely that ICP in microgravity is significantly higher than that experienced lying down on earth. If the integrity of the barrier is reduced in microgravity then it is possible that intracranial hypertension causes some of the symptoms of Space Adaptation Sickness

26. References 1.D. Leszczynski, S. Joenvaara, J. Reivinen, and R. Kuokka: Non-thermal activation of the hsp27/p38MAPK stress pathway by mobile phone radiation in human endothelial cells: Molecular mechanism for cancer- and blood-brain barrier-related effects. Differentiation 70: 120-129 (2002). 2.D. Leszczynski, R. Nylund, S. Joenvaara, and J. Reivinen: Applicability of discovery science approach to determine biological effects of mobile phone radiation. Proteomics 4: 426-431 (2004). 3.S. Stevens, W. Lakin, and P. Penar: Modeling steady-state intracranial pressures in supine, head-down tilt, and microgravity conditions. Aviat Space Environ Med 76:329-38 (2005)

27. Extra Slides

28. Another Example One-way

29. Another Example

32. Radiation Effects on BBB Recent experiments on Earth by Leszczynski et al. involving cell phone radiation demonstrate the potential effect that exposure to even small amounts of radiation in space can have on the blood- brain barrier [1,2]. As reported in these studies, the mobile phone radiation activated non-thermal transient changes in the protein expression levels of hsp27 and p38MAPK in human endothelial cells. It is hypothesized in [1] that activation of hsp27 may cause an increase in blood-brain barrier permeability through stabilization of endothelial cell stress fibers. Increased protein activity may even cause the endothelial cells themselves to shrink, lessening their volume, widening the junction gap, and reducing the overlap region. As a result, radiation exposure in space appears capable of adversely impacting the integrity of the blood brain barrier.