fMRI: Biological Basis and Experiment Design Lecture 3 Cell metabolism Vascular architecture Blood flow regulation Harrison, Harel et al., Cerebral Cortex 12:225 (2002)
Oxidative vs. anaerobic metabolism Non-oxidative (glycolysis) TCA Nucleus mitochondrion Oxidative (16 times more ATP) glc pyr lac
Fox and Raichle Surprise finding suggests that neuronal activity elicits anaerobic metabolism Fox and Raichle, 1986: CBF >> CMRO 2 CBFCMRO 2 OEF
The Magistretti Hypothesis Astrocytes anaerobically metabolize glucose to lactate Neurons aerobically metabolize lactate/pyruvate Magistretti (2000) Brain Research 886:108
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
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
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: 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
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, Mintun, Vlassenko, Rundle, Raichle (2004). Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. PNAS, 101 (2),
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
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
Harrison, Harel et al., Cerebral Cortex 12:225 (2002)
100 m
50 m
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: m
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 5m5m
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)
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