Cerebrovascular Regulation

The project aims at understanding the molecular and biochemical mechanisms, by which the brain adapts local blood flow to neuronal activity and cellular metabolism with high temporal and spatial resolution. A tight relation exists between neuronal and glial cell activation, cerebral energy metabolism, and cerebral vasculature – a phenomenon known as neurometabolic and neurovascular coupling. This tight coupling of electrical and metabolic activity, and regional cerebral blood flow is characteristic for the brain.

Increased neuronal, and thereby metabolic activity of the cerebral cortex during functional activation is accompanied by a transient increase in local cerebral blood flow and by vascular hyperoxygenation [1,2] (Figure 1). In our recent work, we have shown that under physiological conditions there is no evidence for early hemoglobin-deoxygenation at the onset of increased neuronal activity [2,3]. It can be suggested that neurovascular coupling is tight and rapid, possibly serving to protect brain tissue from any period of hypo-oxygenation. Moreover, neurovascular coupling arouses fundamental questions about cerebral blood flow and metabolism: How does the vasculature serve brain function? How do neurons and blood vessels communicate? What specifically makes neurons run?

Functional Magnetic Resonance Imaging (fMRI) is widely used to visualize human brain activity. Its powerful potential to generate 3-D activation maps of the working brain noninvasively has made fMRI the predominant neuroscience method to explore human brain function. However, this method does not measure neuronal activity directly. Instead, it is based on the local adaptation of blood flow that occurs in areas of changed neuronal activity. Neurovascular coupling determines the relationship between neuronal activity and fMRI brain maps. Its purpose and mechanism is far from being resolved. For a correct interpretation of fMRI a precise understanding of this relationship between neuronal activity and local blood flow regulation is crucial. One of our projects aims at better understanding the quantitative relationship between neuronal activity, oxygen consumption and blood flow as the basis for functional brain imaging.

Only little is known about the mediators of neurovascular coupling. The involvement of the highly diffusible vasodilator bioradical nitric oxide (NO) in the regulation of regional cerebral blood flow is widely accepted. In our work, we have shown that NO acts as a modulator rather than a mediator of vascular relaxation due to functional activation in the cerebral cortex, permitting vasodilation mediated by other, still unknown substances. Potassium channels of vascular smooth muscle cells may be possible targets of NO modulation [4,5,6]. It has recently been suggested that the mediator of neurovascular coupling is released not by neurons or glial cells but by intravascular processes (Stamler et al., Science, 1997). We are currently investigating the role of hemoglobin-deoxygenation induced blood-born mediators in neurovascular coupling.

In disease impaired cerebrovascular regulation leads to a mismatch of regional cerebral blood flow and metabolic demand which may itself contribute to tissue damage. We are investigating the 'fingerprints' of physiological or pathophysiological processes in vascular reactivity, cerebral blood flow or hemoglobin oxygenation as the basis for new diagnostic strategies in acute and chronic CNS disorders [7, 8].
The above mentioned topics are approached with different, independent methods to measure cerebral blood flow in relation to the underlying neuronal activity in a rat model in vivo. Functional activation is performed by somatosensory stimulation (whisker deflection or electrical forepaw stimulation [1,9]). We use high-field-fMRI (7T Bruker PharmascanÆ, Figure 2), Optical Imaging (Filterwheel-Spectroscopy combined with LASCA, Figure 3), Microfiber-Spectroscopy and Laser Doppler Flowmetry to obtain information about CBF (cerebral blood flow) and CBO (cerebral blood oxygenation) changes in the rat somatosensory cortex. SEPs (somatosensory evoked potentials) are obtained at the same time to monitor neuronal activity. In order to address questions of vascular regulation directly we have established an isolated artery model (Figure 4).

a) Superimposed on an anatomical image (grayscale, T2-weighted Spin Echo) is an activation map consisting of voxels with statistically significant intensity increase during forepaw stimulation (duration 8s) in a series of T2*-weighted Gradient Echo Images. There is activation in the contralateral somatosensory cortex. b) Time course of the BOLD-Signal within the area of activation, averaged across 10 stimulations (gray box = Stimulation period). Forepaw Stimulation results in a local blood flow increase hyperoxygenating the sample volume.