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Spatial and Temporal Characteristics of the Functional Hemodynamic Response: Insights from fMRI and Two-Photon Microscopy

Afonso C. Silva, Jeff H. Duyn and Alan P. Koretsky

Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda , USA

The coupling between electrical activity and cerebral hemodynamics forms the basis of modern functional neuroimaging techniques, such as functional MRI, positron emission tomography, and optical imaging of intrinsic signals. Via the neurovascular coupling, local changes in electrical activity are accompanied by regional changes in cerebral blood flow (CBF), blood volume (CBV), and blood oxygenation, physiological quantities that act as surrogate markers of increased brain activity. This functional hemodynamic response (HDR) consists of several concomitant and consecutive processes with different timescales and spatial profiles. Characterization of such processes is of fundamental importance for proper interpretation and use of the HDR signals to study brain function.


Our laboratory has been particularly interested in investigating the spatial and temporal characteristics of the HDR, both in small animal models of brain functional activation, as well as in humans. At the microscopic level, the use of two-photon microscopy ( 2PM ) has enabled direct visualization of individual blood vessels. Using 2PM , we have been looking at vessel diameters, transit-times of fluorescent dextrans and red blood cells (RBC) velocities in individual capillaries traversing the top 200 m m of somatosensory cortex, to understand the spatial and temporal evolution of the changes in the cerebral microcirculation elicited by mild hypercapnia. We have observed that the response of the cerebral microvasculature to modest increases in PaCO2 is spatially heterogeneous. While the maximal relative dilatation occurs in the smallest capillaries (1.6 – 4.0 m m resting diameter), the average increase in RBC velocities was larger in medium and large capillaries (4.4 – 6.8 m m resting diameter). Our conclusions are that changes in capillary RBC velocities are spatially dissociated from the observed volumetric changes, and occur to homogenize CBF along capillaries of all diameters. At the macroscopic level, we have resorted to fMRI techniques to measure BOLD, CBF and CBV responses to brain activation, combined with measurements of evoked potentials as a means of tracking the neuronal activity. Previously, we have measured BOLD onset-times to electrical stimulation of the rat forepaw in an attempt to sort out neuronal signaling within laminar structures of the brain. We observed a consistent spatial heterogeneity of fMRI onset-times and amplitudes across the cortical laminae. The earliest onset-time corresponded anatomically to layer IV, with superficial and deeper layers starting significantly later, in accordance with the expected laminar flow of neuronal events. More recently, we have been measuring the BOLD and CBV impulse response (IR), which also show spatially distinct amplitude and temporal characteristics. Unlike CBV, the BOLD IR clearly shows contamination by large draining veins. Interestingly, the CBV IR does not return to baseline for a long time, consistently with other CBV-based fMRI studies in rats. The CBV IR is narrower and peaks earlier than the BOLD IR, thus affording improved temporal resolution. Taken together, these investigations into the spatial and temporal characteristics of the HDR are leading to novel and exciting applications, such as monitoring of subcortical processes.