Model of Blood–Brain Transfer of Oxygen Explains Nonlinear Flow-Metabolism Coupling During Stimulation of Visual Cortex

Abstract

The coupling between cerebral metabolic rate of oxygen (CMRO2) and blood flow (CBF) in response to visual stimulation was evaluated by means of a model of oxygen delivery. The model predicted a nonlinear relationship between stimulus-evoked changes of oxygen consumption and blood flow. The magnitude of the CMRO2/CBF ratio index (IO2) was used to indicate the degree of flow-metabolism coupling prevailing in specific areas of the brain during physiological stimulation. Therefore, the index provided a measure of the blood oxygenation level dependent (BOLD) magnetic resonance contrast. To evaluate the changes of IO2 in response to visual stimulation, the model was applied to the effect of a changing flicker rate of a visual stimulus on the magnitudes of CBF, CMRO2, and oxygen diffusion capacity, in the human brain. Positron emission tomography (PET) was used to measure the CBF and the CMRO2 in 12 healthy volunteers who viewed a cross-hair (baseline) or a yellow-blue annular checkerboard reversing at frequencies of 1, 4, or 8 Hz. The magnitude of CBF in the primary visual cortex increased as a function of the checkerboard reversal rate and reached a maximum at the frequency of 8 Hz (z=16.0), while the magnitude of CMRO2 reached a maximum at 4 Hz (z=4.0). Therefore, the calculated IO2 was lower at 8 Hz than at 1 and 4 Hz, in contrast to the oxidative metabolic rate that reached its maximum at 4 Hz. The model explained the increase of oxygen consumption as the combined effect of increased blood flow and increased oxygen diffusion capacity in the region of visual activation.

The Oxygen Paradox of Neurovascular Coupling

“…However, at 8 Hz stimulation frequency, CMRO 2 increase was only 5% whereas the CBF increase reached 42%. 78 This PET observation has been confirmed with MRI by Lin et al 98 Other studies have found tight coupling of CBF and CMRO 2 with varied stimulus paradigms. For example, in a recent study, Leontiev et al 99 did not find a significant difference in CBF/CMRO 2 coupling between two visual stimuli that activate different neuron populations characterized histologically by differences in cytochrome c distribution.…”

“…of arterial blood 9,000 nmoL/mL Glucose conc. of arterial blood 5,000-6,000 nmoL/mL 53 Oxygen extraction fraction 30%-55% 3,5,6,27,75,93 Glucose extraction fraction 8%-15% ATP concentration of brain tissue 1,000-3,000 nmoL/mL 124,137,138 Total ADP concentration of brain tissue 300 nmoL/mL 124,138 Free ADP concentration of brain tissue 30-35 nmoL/mL [121][122][123] PCr concentration of brain tissue 4,000-5,000 nmoL/mL 123,124,138 Diffusion constant for O2 in brain 78 Assuming mitochondrial oxygen tension close to zero (meaning so low that any further reduction would limit oxidative metabolism), the driving force for oxygen delivery, the gradient between the capillary and mitochondria, can only be increased by an increase in capillary oxygen tension, which in turn requires a decrease of the oxygen extraction fraction. Later, the observation of constant CMRO 2 during pharmacological reductions of CBF led to a modification of the model by incorporating potential changes of cytochrome c oxidase affinity to oxygen during increases in neuronal activity.…”

The Effects of Transit Time Heterogeneity on Brain Oxygenation during Rest and Functional Activation

“…Previous studies have shown that conventional compartment models cannot be fitted to experimental data unless oxygen transport characteristics (dubbed 'PS area product', 'effective diffusivity', 'diffusion capacity', or 'conductance') are allowed to vary during physiologic stimuli. 8,9,12,14 It has been suggested that increased capillary oxygen tension, hematocrit, changes in blood volume, or capillary recruitment 8,9,14 may explain these observations, but the existence of such mechanisms remains controversial. 11 Debates over whether the oxygen conductance/PS product, in this case for oxygen, can change during functional activation typically emerge from structural interpretations of this quantity.…”

“…They speculated that such variations in oxygen conductance are linked to differences in CBF response, and possibly subject to local regulation. 9 The models above assumed negligible oxygen tension (pO 2 ) in tissue, whereas measurements suggest that interstitial pO 2 in brain tissue is in fact roughly 25 mm Hg, albeit with high microregional heterogeneity. 5 Tissue pO 2 affects the oxygen concentration gradient between blood and tissue, and therefore net oxygen extraction.…”

From Blood Oxygenation Level Dependent (BOLD) Signals to Brain Temperature Maps

“…Several works have modelled the relationship between ( ) m t and ( ) f t (Buxton and Frank, 1997;Hyder et al, 1998;Vafaee and Gjedde, 2000;Zheng et al, 2002;Takuya et al, 2003). Particularly, the oxygen limitation model proposed by Buxton and Frank (1997) has been widely employed as part of biophysical models of the generation of the BOLD signal (Buxton et al, 1998;Friston et al, 2000;Friston et al, 2003;Babajani and Zoltanian-Zadeh, 2006;Riera et al, 2006;Riera et al, 2007;Babajani et al, 2008;Blockley et al, 2009):…”