Elsevier

NeuroImage

Volume 30, Issue 2, 1 April 2006, Pages 377-387
NeuroImage

Noninvasive quantification of cerebral blood volume in humans during functional activation

https://doi.org/10.1016/j.neuroimage.2005.09.057Get rights and content

Abstract

Like cerebral blood flow (CBF), cerebral blood volume (CBV) is an important physiological parameter closely associated with brain activity and thus, noninvasive quantification of CBV during brain activation provides another opportunity to investigate the relationship between neuronal activity and hemodynamic changes. In this paper, a new method is presented that is able to quantify CBV at rest and during activation. Specifically, using an inversion recovery pulse sequence, a set of brain images was collected at various inversion times (TIs). At each TI, functional images were acquired with a block-design visual stimulation paradigm. A biophysical model comprised of multiple tissue components was developed and was utilized for the determination of CBV using the visual stimulation data. MRI experiments on five healthy volunteers showed that CBV was 5.0 ± 1.5 ml blood/100 ml brain during rest and increased to 6.6 ± 1.8 ml blood/100 ml brain following visual stimulation. Furthermore, experiments with visual stimulation at two frequencies (2 and 8 Hz) showed that the increases in CBV correlated with the strength of stimulation. This technique, with its ability to measure quantitative CBV values noninvasively, provides a valuable tool for quantifying hemodynamic signals associated with brain activation.

Introduction

Functional magnetic resonance imaging (fMRI) techniques based on local cerebral hemodynamic changes have been used extensively for mapping functional neuroanatomy (Ogawa et al., 1990, Belliveau et al., 1991, Detre et al., 1992). Although there are emerging methods to measure changes in the MRI signal directly caused by neuronal action potentials (Bodurka and Bandettini, 2002, Xiong et al., 2003), the vast majority of fMRI experiments measure changes in cerebral blood oxygenation (Ogawa et al., 1992, Kwong et al., 1992, Bandettini et al., 1992, Frahm et al., 1992), blood flow (Williams et al., 1992, Edelman et al., 1994, Kim, 1995, Kwong et al., 1995), or blood volume (Belliveau et al., 1991, Mandeville et al., 1998) as an indirect measure of neuronal activity. Hemodynamic-based fMRI signals have different characteristics in terms of sensitivity and specificity in detecting brain activity. Techniques based on BOLD (blood oxygenation level-dependent) contrast usually have higher sensitivity; however, physiological interpretation of the BOLD signal is limited since the signal arises from the complex interplay of blood volume, flow and oxygen consumption (Ogawa et al., 1993, Boxerman et al., 1995, Buxton et al., 1998, van Zijl et al., 1998). Perfusion imaging with arterial spin labeling (ASL) provides quantitative measurement of cerebral blood flow (CBF) that targets signal changes more closely associated with neuronal activity compared to the relatively venous-weighted blood oxygenation. However, sensitivity of current ASL perfusion techniques is inherently low due to the low perfusion-related contrast (∼1%) and the image subtraction procedure (Wong et al., 1997). The earliest human fMRI experiment was performed with injections of exogenous susceptibility contrast agents (Belliveau et al., 1991). Although this method has not been widely used in human studies, primarily due to the invasiveness of the technique and the short half-lifetime of Gadolinium (Gd)-based contrast agents, it has been successfully employed in animal fMRI experiments utilizing the much longer half-lifetime monocrystalline iron oxide nanocolloid (MION) (Mandeville et al., 1998). Recently, a noninvasive fMRI technique based on CBV changes during brain activation was proposed (Lu et al., 2003), in which MR signals of blood water were suppressed by acquiring images at the blood-nulling point of an inversion recovery sequence to detect vascular space occupancy (VASO)-dependent signal changes associated with brain activation. VASO imaging is expected to have better spatial specificity than BOLD due to its high sensitivity to microvessels, but it cannot obtain quantitative CBV information during activation without additional baseline CBV data.

Noninvasive quantification of CBV and its change during physiological challenges promise to improve our understanding of brain hemodynamics and fMRI signal mechanisms, including evaluating potential alterations of vascular state versus neuronal activation following drug administration (Salmeron and Stein, 2002). However, CBV imaging with injections of exogenous contrast agents is an invasive method and is not suitable for fMRI studies with complex stimulation paradigms (Belliveau et al., 1991), while VASO imaging detects CBV-weighted signal changes between rest and activation states, but does not provide absolute CBV values at these two states (Lu et al., 2003).

We present here a new method that is able to quantify CBV noninvasively at rest and during activation. This was achieved by measuring fMRI signal at various inversion times (TI), thereby varying the weightings of CBV and blood oxygenation contrasts. The data were fitted to a biophysical model comprised of multiple tissue components to obtain absolute CBV at rest and following activation. Functional experiments with graded visual stimulation were conducted on healthy volunteers to evaluate this method.

Section snippets

Biophysical model for determination of CBV and blood oxygenation

A three-compartment model was used, in which a voxel in the activated region contains FCSF fraction of cerebral-spinal fluid (CSF) and 1-FCSF fraction of brain parenchyma. The parenchyma, in turn, contains fb fraction (also known as CBV) of blood and 1-fb fraction of extravascular tissue. Note that the volume fraction of the blood in the whole voxel is given by:Fb=(1FCSF)·fb

The MR signal magnitude can be written as:S=abs(SCSF+Sb+St)where Si (i = CSF, b or t) is the signal contribution from the

Results

Experimental SNRs (SNRvoxel) were dependent on TI: 144 ± 44 (n = 5, mean ± SD), 54 ± 14, 39 ± 14, 38 ± 9, 33 ± 6, 29 ± 10, 25 ± 4, 34 ± 12, 38 ± 9, 54 ± 16, 67 ± 15, 69 ± 16, 84 ± 11, and 91 ± 15 for TI values of 499 ms, 649 ms, 679 ms, 709 ms, 724 ms, 769 ms, 799 ms, 829 ms, 859 ms, 889 ms, 919 ms, and 949 ms, respectively. Fig. 2a illustrates a representative set of activation maps from the visual stimulation experiments of one subject acquired at 14 different TIs. While activated voxels are

Discussion

We have developed a noninvasive method to quantify absolute CBV values in human at rest and during functional activation. With measurements of functional signals at various TIs, CBV parameters were determined based on a biophysical model. The applicability of this method was demonstrated using visual stimulation.

CBV is an important parameter in brain physiology and is of clinical value for many neurovascular diseases as well as some diseases of non-vascular origin (e.g., brain tumor,

Conclusion

In summary, we have developed a new MRI method for noninvasive quantification of CBV in humans. Absolute CBV at rest and during activation can be obtained by fitting a series of fMRI data sets acquired at various TIs to a biophysical model. Experiments on healthy volunteers with visual stimulations demonstrated that the obtained CBV values are consistent with previous reports. This technique provides a useful tool for quantifying hemodynamic changes associated with neuronal activity.

Acknowledgments

The authors are thankful to Dr. Peter van Zijl for providing blood R2* values at 3.0 T.

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