Transport Phenomena in the Human Central Nervous & Musculatory Systems

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1 Transport Phenomena in the Human Central Nervous & Musculatory Systems John G. Georgiadis Mechanical Sci. & Eng. Dept and Beckman Institute University of Illinois at Urbana-Champaign 1

2 Mass Transport in CNS and Muscles Important for healthy, longer life span Central Nervous System NIH Vis. Hum. Axonal Connectivity Blood/O2 Supply Skeletal Muscles Intra-muscular Transport Fuel ATP Myofibrils (Honecker) 2

3 Background Central Nervous System Hierarchy Neuro-Vascular Unit (NIH Vis. Hum) 1 mm 10 µm 1 µm (Cassot) (Abbott) (Georgiadis) 3

4 Societal Impact (Central Nervous System) Clinical diagnosis or (Olivero). intervention Neuro-vascular diseases Stroke Cancer Trauma Neuroscience Drug discovery (Wang) Body (core) temp. Brain temp. Cooling helmet and cortical temperature Permeability of CNS 4

5 Technical Principles in φ1 MRI θ1 diffusion-weighted q dw-mri NIRS q q L mol-1 cm-1 Molar absorptivity (ε) frequency domain q, HHb HbO nm (Michalos) 2 a2 (Georgiadis) NIRS Therapeutic spectral window 800 nm Wavelength H nm 5 (Karampinos)

6 State-of-the-Art (Sutton) Corona radiata Cortico-spinal tract Neural tractography MRI MRI (Arfanakis) Functional Imaging f-mri, NIRS Cerebro-vasculature Visual cortex tumor CT Medial cerebral arteries Microscopy CT 6 (Karniadakis)

7 State-of-the-Art Blending CNS diffusion physics with MRI Human pons Y Rat spine (Raguin) Infusion site Blood vessels (Gujrati) (Sarntinoranont) 7

8 State-of-the-Art Near Infrared Spectroscopy (frequency domain) for motor cortex activation map [HHb] (µm) Reflected Collected Absorbed Data acquisition frequency = 1.25Hz Light in BB 5 AA (Michalos) 8

9 State-of-the-Art Microcirculation redistribution Photo-thrombotic clotting (rat cortex) Cortical arteriolar network quickly redistributes collateral flow to mitigate vessel obstruction effects (Schaffer) 9

10 Open question: Potential routes for transport across the bloodbrain barrier (Abbot) (Hawkins) 10

11 Barriers (Central Nervous System) Trade-off between imaging speed and spatial resolution (need <100 µm) Cortical surface microscopy for animal models Catheters, MRI, CT, or NIRS for humans Immuno-histology for autopsied tissues Gaps in knowledge regarding physiological mechanisms Microcirculation redistribution Blood-brain barrier function Paucity of controlled cerebral perfusion experiments 11

12 Societal Impact (Transport in Muscle) Obesity and Type II Diabetes Intramyocellular triglycerides insulin resistance Physical Rehabilitation Spine injuries Aging Sarcopenia MRI section of adult thighs 12 (Evans)

13 Background Lipid (IMCL) single muscle fiber Adipocyte (EMCL) single muscle fiber Skeletal Muscles Hierarchy Fuel (lipid-carb) storage 610 magn. 1 µm (Lossnitzer) (Marieb) (Evans) 13

14 Metabolism in muscle Passive and Active Transport Mitoch ATP Myofibrils (active) Mitoch PCr Myofibrils (passive) 14 (Lossnitzer)

15 Adaptation to energy demand Skeletal Muscles Intra-myocellular lipids Capillary networks (Ordered) mitochondria networks Mitochondria Lean Obese (Vendelin) Before training After 15 (Malefant)

16 MRI and MRS of human calf (King) Tibia EMCL IMCL Soleus muscle H NMR Chemical Shift -CH21 (Karampinos) IMCL ppm 16

17 Barriers Morphological, functional, and metabolic imaging Ultrasound for fast morphological imaging MRI and MRS provide good non-invasive modalities but require immobilization Lack of knowledge regarding intrinsic muscle function at the intra- or extra-myocellular levels Regulation of muscle oxygen supply to match demand Metabolic compartmentalization in myocyte not a wellmixed bag of water Validation of models Immuno-histology on percutaneous muscle biopsies NMR 17

18 Recommendations 1. Launch both technology- and hypothesis-driven research efforts focusing on transport phenomena in the Central Nervous System and Muscle (alliances with NIH, neurosurgeons, kinesiologists, etc) 2. Invest in fast, non-invasive, quantitative imaging techniques couple to models for CNS and muscle transport 3. Validate mechanistic models (active transport, autoregulation, emergence, metabolic pathways, morphogenesis, networks, redundancy, stochasticity) 18

19 References* *All primary authors or sources are also given in parenthesis near each image 1. Abbott J et al., Nature Rev. Neuroscience 7:41-53, Abbott J, Drug Discovery Today: Technologies 1(4): , Cassot et al. Microcirculation 13, 1-18 (2006) 4. Georgiadis JG 5. Hawkins T & Davis TP, Pharmacol Rev 57: , Honecker S, PhD Thesis, University of Illinois, Karampinos et al. ISMRM Malefant P et al., Int. J. Obesity 25, , Marieb EN, Human Anatomy & Physiology 5th ed, Addison Wesley, Raguin LG et al., ISMRM Sarntinoramont M, Ann. Biomed. Eng, 34(8): , Schaffer C et al. PLoS Biology, 4(2): , Sutton B et al. ISMRM Vendelin M et al., Am J Physiol Cell Physiol 288: C757 C767, Wang H et al., J Neurosurg 100: , 2004 Support by NSF (CTS , DMI ) and NIH (R21-EB005695) is acknowledged 19