Linearity of blood-oxygenation-level dependent signal at microvasculature.

The relationship between the blood-oxygenation-level dependent (BOLD) signal and its underlying neuronal activity is still inconclusive. The task of completely understanding this relationship has been encumbered not only by the complexity of neuronal responses, but also by nonlinear characteristics of the vascular response that are not correlated to neural activity. Repeated stimuli inducing replicable neural responses led to successively smaller BOLD amplitudes and delayed BOLD onset latencies when inter-stimulus intervals (ISIs) are shorter than 4-6 s, indicating significant nonlinearity between the BOLD signal and the underlying neuronal activity. We have provided evidence that large-vessel BOLD contributions could be the source of the nonlinearity (Zhang, N., Zhu, X.H., Chen, W., 2008b. Investigating the source of BOLD nonlinearity in human visual cortex in response to paired visual stimuli. Neuroimage 43, 204-212). By utilizing the spin-echo (SE) BOLD fMRI method at high magnetic fields to suppress large-vessel BOLD contributions, we found that the BOLD signal from the micro-vascular activity is replicable in response to replicated neuronal activities even at ISIs as short as approximately 1 s, suggesting that the micro-vascular BOLD activity is essentially a linear system. These results indicate that micro-vascular BOLD signals should provide an accurate estimate of the amplitude of neuronal activity changes. Consequently, the findings are important in understanding and resolving the controversy in the neurovascular coupling relationship. In addition, the difference in BOLD response times between macro- and micro-vascular activities demonstrated herein will have a significant impact on functional connectivity and causality studies. Moreover, SE fMRI at high fields, due to its capability of accurately representing the strength of neural activity as well as its previously shown high spatial specificity to activated brain regions, is an ideal choice for mapping brain function and quantifying the stimulus-evoked brain activity noninvasively.