Cerebral Microvascular Blood Oxygenation Changes during Increased Neuronal Activity

to tissue is limited at rest. Therefore a larger increase in CBF is required to support the smaller increase of oxygen metabolism, because the oxygen extraction fraction is significantly dropping with increased red blood cell velocity [7]. A typical example of microvascular blood oxygenation (A) and hemoglobin oxygen saturation (B) changes due to functional activation by whisker hair deflection in the anesthetized rat is provided in Figure 2.

Early Cerebral Microvascular Blood Oxygenation Changes during Increased Neuronal Activity

Despite intense research efforts a number of unresolved issues exist regarding functional activation-induced changes in oxygen consumption and delivery. Most investigators agree on the principal features of blood oxygenation changes more than 2 seconds after stimulation onset. However, early oxygenation changes, preceding the rCBF

Cerebral Microvascular Blood Oxygenation Changes Induced by the Regional Cerebral Blood Flow Response during Increased Neuronal Activity

Changes of hemoglobin oxygenation during neuronal activity can be investigated by methods measuring reflection changes followed by spectroscopic analysis of light received from the cortex illuminated with light in the visible wavelength range in experimental animals or in the near-infrared wavelength range in humans. The principle features of changes in oxy- and deoxyhemoglobin during increased brain activity is comparable in animals and humans. Coun-terintuitively, the stimulation-induced changes in oxy- and deoxyhemoglobin result in regional hyperoxygenation of the blood and, hence, an increase in hemoglobin oxygen saturation. Oxyhemoglobin concentration starts to increase within the first 1 to 2 seconds of stimulation onset and reaches its maximum 2 to 3 seconds later followed by a plateau during ongoing activity. When stimulation stops, oxyhemoglobin concentration returns to baseline within several seconds followed by a transient small undershoot. Deoxyhemoglobin concentration starts to decrease approximately 2 to 3 seconds after stimulation onset and peaks 2 to 3 seconds later. At the end of stimulation deoxyhemoglo-bin also returns to baseline followed by a transient overshoot. Beside an increase in hemoglobin oxygenation during functional activation, a significant increase in partial molecular oxygen pressure within the microcirculation can be detected. The time course of microvascular Po2 changes exactly match that of oxyhemoglobin during increased neuronal activity [3, 6]. With neuronal activation the fractional change in regional CBF leading to blood hyperoxygenation is approximately twice as large as the fractional change in oxygen metabolism, and both are coupled through a linear relationship that does not depend on stimulus type. It can be suggested that oxygen delivery from brain microcirculation

ra 75

I 70

t 65

x 10J

amplitude e g 9 e

e so 100 time [ms|

/ oxyhemoglobin J — deoxyhemoglobin total hemoglobin

\ oxygen saturation

V

Figure 2 Typical example of microvascular blood oxygenation (A) and hemoglobin oxygen saturation (B) changes due to functional activation by 4 seconds of whisker hair deflection (3 Hz) in the anesthetized rat. Regional cerebral oxygenation changes are measured by microfiber spectroscopy (wavelength range 510 to 805 nm, wavelength-dependent differential path-length corrected analysis, estimated hemoglobin concentration 20 ||M, mean saturation 60 percent as determined for microcirculatory areas). Total hemoglobin and hemoglobin oxygen saturation changes are calculated from measured oxy- and deoxyhemoglobin changes. Neuronal activity was recorded as somatosensory evoked potentials (SEP). The SEP (average of 4 seconds of 3-Hz stimulation) responsible for the hyperoxygenation response is provided in the small inset in part A of the figure. During functional activation, oxyhemoglobin increases and deoxyhemoglobin decreases, leading to microvascular hyperoxygenation and an increase in hemoglobin saturation. The blood oxygenation changes are temporally tightly coupled to the somatosensory stimulation. (see color insert)

response leading to hyperoxygenation, are controversial. The existence of an early hemoglobin deoxygenation within the first seconds after stimulation onset seems highly elusive. The phenomenon of an early deoxyhemoglobin increase has been termed initial dip, since it is detected as a decrease in the magnetic resonance imaging signal induced by an increase of deoxyhemoglobin, which has—in contrast to oxyhemoglobin—paramagnetic properties and can be used as an endogenous paramagnetic contrast agent. Whereas some studies have shown an early increase in deoxyhemoglobin preceding the onset of the CBF response [8, 9], other studies argue against the occurrence of an early loss of hemoglobin oxygenation and decrease in microvascular Po2 that precede the rise in CBF [3, 10]. From further studies in cats and rats it can be concluded that the detection of an early dip mainly depends on the hemodynamic properties. Strong evidence exists for a correlation of the occurrence of an early increase of deoxyhemoglobin and the temporal onset of the regional CBF response, which very much parallels the oxyhemoglobin increase. Hypothetically, a lower baseline CBF and thus lower mean transit time of red blood cells through the cerebral microvasculature may favor a condition in which oxygen delivery lags oxygen extraction. In addition, a correlation of an early deoxyhemoglobin increase and the systemic arterial pco2 may exist in humans as well as in animal experiments. The obvious variability of occurrence, amplitude, and rise time of the dip in experiments in cats and monkeys may also depend on the anesthetic and on the depth of anesthesia. Consequently, the early dip has a low overall contrast-to-noise ratio. Its occurrence seems to be highly susceptible to subtle changes of basal physiological condition, and it may thus not be detectable under physiological conditions. In principle, the existence of an early increase in deoxyhemoglobin at the onset of functional activation would suggest that early metabolic changes in the brain during increased neuronal activity are oxidative. An early desaturation of hemoglobin might support the hypothesis of oxygen tension-related mechanisms within the tissue triggering yet unknown signals to the vasculature to induce vasodilation. However, it is still unresolved whether increases in regional CBF and oxygen consumption are dynamically coupled following neural activation or occur in parallel and independent from each other.

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