Spatiotemporal evolution of the functional magnetic resonance imaging response to ultrashort stimuli

Abstract

The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, whereas long stimuli lead to the involvement of remote vascular supply and drainage. Here, we used functional magnetic resonance imaging to investigate the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in an anesthetized rodent model. The HRFs to a single 333-μs-long stimulus were robustly detected and consisted of a rapid response in both CBF and CBV, with an onset time (OT) of 350 ms and a full width at half-maximum of 1 s. In contrast, longer stimuli elicited a dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolonged the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released, and effective within 350 ms. However, the difference between the BOLD and CBV OT (∼100 ms) was significantly smaller than the arteriolar-venular transit time (∼500 ms), indicating an arterial contribution to the BOLD HRF. Finally, 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. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain.

Figure 1.

A, BOLD t score maps at different stimulus durations in two typical subjects. The active regions grew with stimulus durations of up to three pulses (1 s). B, Time courses of the BOLD HRF to stimuli of increasing durations, averaged across subjects (n = 8). C, Peak BOLD amplitude (top graph) and area under the curve (bottom graph) in each laminar ROI. In all layers, the peak BOLD amplitude increased with stimulus duration, reaching 90% of its maximum value at stimulus duration of six pulses (2 s), after which it did not grow further. Error bars indicate 1 SD.

Figure 2.

A, Functional incidence maps for the BOLD, CBF, and CBV HRF to different stimulus durations (n = 9). Active pixels represent the locations that consistently (for at least 1 s) clear 1 SD above the mean signal of the prestimulus period, colored according to the number of animals that show a response at that location. B, Laminar time courses of the BOLD, CBF, and CBV HRF to stimuli of increasing durations, averaged across subjects (n = 9). For all modalities, the peak amplitude was larger in layers I–III and IV–V than in layer VI. The CBF HRF showed both a quick onset and quick offset in response to all stimulus durations. The CBV HRF displayed a prolonged and slowly decaying offset tail, which was visible for stimulus durations as short as three pulses (arrows). Error bars indicate 1 SD.

Figure 3.

A, Mean onset time maps for the BOLD, CBF, and CBV HRF, averaged across subjects (n = 9) after spatial normalization to the rat brain atlas space (see Materials and Methods). The shortest onset times occurred in the middle cortical layers, whereas the longest onset times occurred in layer VI and in the adjacent cortical regions. B, Graph of the mean onset times for the BOLD, CBF, and CBV HRF, averaged over all stimulus durations and across subjects (n = 9) as a function of the cortical depth. For all three functional modalities, the onset times in layer VI were consistently longer than in other layers. Across modalities, the CBV onset times in layers I–III and IV–V were significantly shorter than the respective BOLD onset times. Error bars indicate 1 SD. *p < 0.05.

Figure 4.

BOLD, CBF, and CBV HRF to stimulus durations of one pulse (left) or six pulses (right), averaged across subjects (n = 9) and normalized to their respective peak amplitude. The temporal dynamics of the CBF and CBV HRF to a single-pulse stimulus were identical and faster than the evolution of the BOLD HRF in all layers. However, the CBV dynamics were as delayed as the BOLD dynamics in response to the 2 s stimulus, suggesting increased contribution of venules and veins to the CBV HRF to longer stimuli.

Figure 5.

A, Mean TTP maps for the BOLD, CBF, and CBV HRF, averaged across subjects (n = 9) after spatial normalization to the rat brain atlas space (see Materials and Methods). At all stimulus durations, CBF has the shortest TTP, whereas BOLD has the longest. The CBV TTP with brief stimuli is as short as the CBF TTP, but it becomes as slow as the BOLD TTP with long stimuli. B, Plot of TTP versus stimulus duration in different cortical layers for all three functional modalities, averaged across subjects (n = 9). C, Plot of FWHM versus stimulus duration. Error bars indicate 1 SD.