We have a long-standing interest in investigating the spatiotemporal evolution of the hemodynamic response function (HRF) as an important way to understand the role of functional hyperemia in supporting neuronal activity. The determination of both spatial and temporal characteristics of the HDR to focal brain activity is a topic of great relevance as it dictates the accuracy of functional neuroimaging techniques in mapping activation regions, establishes the ultimately achievable spatial and temporal resolution, and influences the interpretation of the data. We are working on optimizing stimulus parameters and measuring, in space and in time, the ensuing HDR, with the long-term goal of determining the ultimate spatial domain of CBF control and its associated temporal evolution. We believe such work will require extremely brief stimuli, delivered under well-controlled conditions, to elicit minute, yet measurable vascular events, which can presumably serve as the building blocks of the integrative CBF response to more complex stimuli. In the current review cycle, we focused on studying the influence of the stimulus duration on the spatiotemporal characteristics of the HRF. Based on the observation that no further increases in peak amplitude of the BOLD HRF occurred for stimulus durations beyond 2s, we set out to determine in further detail the spatiotemporal evolution of the BOLD, CBF and CBV HRF to brief stimulation in the chloralose-anesthetized rat. We observed robustly detectable BOLD, CBF and CBV responses to a single 300us pulse. The rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical depth. Also the temporal characteristics of the BOLD, CBF and CBV HRF were distinct and informative. Of particular note is that the fMRI HRFs are remarkably fast, contrary to the notion of slow CBF responses to neural activity that still perpetuate in the literature. Regions of the cortex containing layers IV and V showed the shortest onset latencies. The CBV onset time of 350ms was the shortest latency, significantly longer than the BOLD onset time of 500ms. To the best of our knowledge these are the shortest onset-times measured to date, and have the very important implication that upon stimulation, vasoactive agents are synthesized and released, diffusing to their site of action to relax the pericytes and smooth muscle cells surrounding blood vessels within very short times. Another noteworthy feature relates to the distinct dependence of each hemodynamic modality of the stimulus duration. The CBF and CBV HRFs to a single 300 us pulse maintain a tight temporal evolution, consisting of equally fast onset, rise, peak and return to baseline. The BOLD HRF was delayed by the transit of oxygenated blood across the capillary network to the venous side of the circulation. In response to a 2s-long stimulus, however, CBF and CBV had both a fast onset, but only the CBF curve displayed its fast rise and peak, while the CBV rise was delayed and evolved towards the also delayed BOLD response, both of them significantly affected by the slow and dispersive transit of oxygenated blood across the cortical microvasculature towards the draining veins. The peak of BOLD and CBV responses happened at the same time. For all stimulus durations, CBF had the shortest TTP, while BOLD had the longest. CBV, on the other hand, behaved like CBF for the shortest stimuli and like BOLD for the longest stimuli. The data obtained offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain, together with some insightful guidance into the use of functional hyperemia to study the brain. Very short stimuli elicit fast changes in CBF and CBV, associated mainly with an active redistribution of blood flow and volume within the capillary network and transient increases in blood flow and volume in arterioles and venules. This small increase in local blood flow is easily accommodated by the local microvasculature, so that the temporal evolution of CBF and CBV matches well, while the BOLD HRF lags behind due to influence of the arteriole-venule transit time on the BOLD signal. Under certain conditions, there may be a small increase in the pre-capillary oxygenation, which would allow an arterial contribution to the BOLD HRF and make BOLD display a fast onset to stimulation. If the stimulus duration is short compared to the net arterial-venous transit time, CBF and CBV maintain a close temporal relationship, as the increase in blood flow and volume is equivalent both during the increased supply of blood upon vasodilatation, as well as during the restoration of blood flow associated with vasoconstriction and drainage down the local venous vasculature. Because of the contained involvement of the local microvasculature alone, functional experiments based on the use of very brief stimulus durations may be ideal in the study of the local, neuronally-derived mediators of neurovascular coupling responsible for the regulation of the CBF response to fast, brief events. As the stimulus duration increases, the sustained neural activity causes larger increases in CBF that engage additional segments of the local vasculature, both on the arterial as well as on the venous side. Arterioles and arteries dilate as vasodilatory signals propagate upstream of the region of activation, increasing local CBF and CBV. When the stimulus duration is sustained beyond the arterial-venule transit time, the post-capillary side of the vasculature starts to collect the increased amount of blood, imposing a continued increase in local CBV. Under these conditions, the temporal evolution of the CBV response starts to be influenced by the passive accumulation of blood in venules and small intracortical veins as it is drained away from the capillary network, departing from the temporal evolution of the CBF HRF and approaching the evolution of the BOLD HRF. Functional neuroimaging experiments performed with intermediate stimulus durations may provide interesting information as to the relative contribution of small arteries and venules to the functional HRF. These stimulus durations have the advantage of producing the highest signal amplitudes and minimal prolonged effects, allowing faster repetition of stimulation epochs. With the sustained stimulation, the arteries and arterioles will dilate to a steady-state value. At this point, the CBF HRF reaches a plateau and the CBV curve switches to a slower rate of increase, dictated by a steady passage of blood through the vasculature with continued drainage on the venous side (thus the CBV dynamics becomes similar to that of the BOLD HRF). Upon cessation of the stimulus, the above scenario reverses. The arterioles and arteries constrict, causing a rapid decrease in CBF and an equally rapid initial decrease in CBV. Once the vessels have returned to their resting tone, the CBF response is back to baseline, while CBV is still elevated due to the slow drainage of blood away from the activated region. Due to the ceased supply of oxygenated blood to the venous side of the vasculature, the BOLD response also returns to baseline and may display an undershoot if the CBV is still largely elevated. Experiments carried out under these conditions of long stimulus durations produce high signal amplitudes, but also have the disadvantage of taking long to reset to the original baseline, necessitating long inter-stimulus intervals and potentially involving interactions between the responses to adjacent epochs, which may complicate the interpretation of results.

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