1. fMRI: Biological Basis and Experiment Design Lecture 3 Cell metabolism Vascular architecture Blood flow regulation Harrison, Harel et al., Cerebral Cortex 12:225 (2002)

2. Oxidative vs. anaerobic metabolism http://personal.nbnet.nb.ca/trevgall/biology/ Non-oxidative (glycolysis) TCA Nucleus mitochondrion Oxidative (16 times more ATP) glc pyr lac

3. Fox and Raichle Surprise finding suggests that neuronal activity elicits anaerobic metabolism Fox and Raichle, 1986:  CBF >>  CMRO 2 CBFCMRO 2 OEF

4. The Magistretti Hypothesis Astrocytes anaerobically metabolize glucose to lactate Neurons aerobically metabolize lactate/pyruvate Magistretti (2000) Brain Research 886:108

5. Capillary pre-capillary arteriole endothelium sm muscle Neurons and astrocytes are cells Astrocyte Neuron 2 LAC + 2 ATP TCA glucose 2 LAC + 2 ATP TCA glucose 32 ATP

6. Capillary pre-capillary arteriole endothelium sm muscle Magistretti hypothesis: an explanation for Fox and Raichle Astrocyte Neuron 2 LAC + 2 ATP TCA glucose 2 LAC + 2 ATP TCA glucose 32 ATP

7. Metabolism in astrocytes and neurons Pellerin: put back in an arrow that went missing (too much disagreement about what role lactate plays for neurons) Attwell & Laughlin (2001). JCBFM 21: 1133-1145. Continued debate about whether (approximately) stoichiometric coupling indicates that glucose uptake is driven by glutamate cycling Continued debate about compartmentalization of oxidative and non-oxidative metabolism in neurons and glia

8. Evidence for compartmentalization of metabolism Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W. (2004). Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science, 305, 99-103. Mintun, Vlassenko, Rundle, Raichle (2004). Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. PNAS, 101 (2), 659-664.

9. Brains are not muscles Pediatric patient (with fungal infection of liver)Adult (showing scar tissue following hernia repair) 18-FDG PET images from Abouzied et al. (2005). J. Nuc. Med. Tech. 33(3):145

10. Capillary pre-capillary arteriole endothelium sm muscle Neurovascular coupling: why energy budgets and oxidative metabolism matter Astrocyte: Inc Ca ++, uptake of glutamate --> (release of NO, EET), increased glucose metabolism (non-oxydative)? Interneuron - inc Ca ++ even w/o spikes - release of NO, EETs … --> dilation - release of NPY, SOM(?) --> contstriction - inc. glc metabolism? Neuron - inc Ca ++ when spiking - release of NO, EETs … - inc. glc metabolism (oxidative)? propagation of dilatory signals autoregulation

11. Harrison, Harel et al., Cerebral Cortex 12:225 (2002)

12. 100  m

13. 50  m

14. On the scale of a voxel Blood is supplied to and drained from the cortex by the pial network –~100 – 500 micron diameter ~half the blood volume is in intracortical veins and arteries (2% gray matter vol.) –~10 – 50 micron diameter –diameter depends on depth ~half the blood volume is in the capillary network (2% gray matter vol.) –~8 micron diameter –density correlates with neural demand White matter is supplied by transcortical arteries and veins Human temporal cortex Reina de la Torre et al (1998) Anatomical Record 251:87 375  m

15. The Plumbers and the Electricians There is no such thing as constant flow –Pulse –Vasculature is highly responsive; can autoregulate The vascular network is not a fixed entity –Flow can switch directions in small vessels and capillaries –Capillaries can grow to match metabolic demand Bottom-up regulation is more practical than top-down 5m5m

16. Balloon Model, Part I: CBF and CBV CBF = cerebral blood flow –increased CBF increases signal strength CBV = cerebral blood volume –increased venous blood volume decreases signal strength F out (t)F in (t)

18. Filling the balloon F out (t)F in (t) where  0 is mean transit time through balloon, resting state  v is mean transit time through expanded balloon v(t) is volume of balloon