The BOLD post-stimulus undershoot, one of the most debated issues in fMRI.

This paper provides a brief overview of how we got involved in fMRI work and of our efforts to elucidate the mechanisms underlying BOLD signal changes. The phenomenon discussed here in particular is the post-stimulus undershoot (PSU), the interpretation of which has captivated many fMRI scientists and is still under debate to date. This controversy is caused both by the convoluted physiological origin of the BOLD effect, which allows many possible explanations, and the lack of comprehensive data in the early years. BOLD effects reflect changes in cerebral blood flow (CBF), volume (CBV), metabolic rate of oxygen (CMRO(2)), and hematocrit fraction (Hct). However, the size of such effects is modulated by vascular origin such as intravascular, extravascular, macro and microvascular, venular and capillary, the relative contributions of which depend not only on the spatial resolution of the measurements, but also on stimulus duration, on magnetic field strength and on whether spin echo (SE) or gradient echo (GRE) detection is used. The two most dominant explanations of the PSU have been delayed vascular compliance (first venular, later arteriolar, and recently capillary) and sustained increases in CMRO(2), while post-activation reduction in CBF is a distant third. MRI has the capability to independently measure CBF and arteriolar, venous, and total CBV contributions in humans and animals, which has been of great assistance in improving the understanding of BOLD phenomena. Using currently available MRI and optical data, we conclude that the predominant PSU origin is a sustained increase in CMRO(2). However, some contributions from delayed vascular compliance are likely, and small CBF undershoot contributions that are difficult to detect with current arterial spin labeling technology can also not be excluded. The relative contribution of these different processes, which are not mutually exclusive and can act together, is likely to vary with stimulus duration and type.