The spatial extent of the BOLD response Ziad S. Saad, a,b, * Kristina M. Ropella, b Edgar A. DeYoe, c and Peter A. Bandettini a a Laboratory of Brain and Cognition, National Institute of Mental Health, NIH, Bethesda, MD 20892-1148, USA b Department of Biomedical Engineering Marquette University, Milwaukee, WI 53233, USA c Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA Received 16 August 2002; revised 29 October 2002; accepted 21 November 2002 Abstract Functional magnetic resonance imaging is routinely used to localize brain function, with multiple brain scans averaged together to reveal activation volumes. In this study, we examine the seldom-studied effect of multiple scan averaging on the extent of activation volume. Using restricted visual field stimulation, we obtained a large number of scan repetitions and analyzed changes in activation volume with progressively increased averaging and across single scans. Activation volume increased monotonically with averaging and failed to asymptote when as many as 22 scans were averaged together. Expansions in the spatial extent of activation were not random; rather, they were centered about activation loci that appear with little or no averaging. Using empirical and simulated data, changes with averaging in activation volumes and cross correlation coefficient distributions revealed the presence of considerably more activated voxels than commonly surmised. Many voxels have low SNR and remain undetected without extensive averaging. The primary source of such voxels was not downstream venous drainage since there was no significant and consistent delay difference between voxels activated at different averaging levels. Voxels with low SNR may reflect a diffuse subthreshold activity centered about spiking neurons, dephasing gradients from distal veins, or simply a blood flow response extending beyond the locus of neuronal firing. Across single scans, as much as twofold changes in activation volume were observed. These changes were not correlated with the order of scan acquisition, subject task performance, or signal and noise properties of activated voxels. Instead, they may reflect subtle changes between overlapping noise and signal frequency components. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Activation volume; Functional magnetic resonance imaging; Visual cortex; MRI methods/techniques Introduction Functional magnetic resonance imaging (FMRI) is a widely used method for mapping human brain function. Through coupling mechanisms that remain a subject of debate, neuronal stimulation induces hemodynamic changes that are detectable by blood oxygenation level-dependent (BOLD) MRI (Bandettini and Ungerleider, 2001; Logoth- etis et al., 2001; Magistretti, 2000; Magistretti et al., 1999; Ogawa et al., 1990a; Villringer, 1997; Villringer and Dirnagl, 1995). To date, many studies of BOLD signal properties have focused on its temporal dynamics and lin- earity and hemodynamic and biophysical models (Arthurs et al., 2000; Bandettini and Wong, 1997; Bandettini et al., 1992; Birn et al., 2001; Boynton et al., 1996; Buxton, 2001; Buxton et al., 1998; Davis et al., 1998; Duong et al., 2000; Friston et al., 1998; Hoogenraad et al., 2001; Kim et al., 1999; Kim and Ugurbil, 1997; Kruggel and von Cramon, 1999a, 1999b; Kwong et al., 1992; Lee et al., 1995; Liu and Gao, 2000; Mandeville et al., 1998, 1999; Marota et al., 1999; Menon et al., 1993; Miller et al., 2001; Ogawa et al., 1990a, 1990b; Ogawa and Lee, 1992; Saad et al., 2001; Vasquez and Noll, 1998; Yacoub et al., 1999). In addition, studies have focused on the spatial localization of the BOLD response relative to the sites of neuronal activation and the limits of its spatial resolution. (Duong et al., 2001; Engel et al., 1997; Segebarth, 1994, No. 149; Goodyear and * Corresponding author. Statistical and Scientific Computing Core, National Institute of Mental Health, 10 Center Dr. Room 1D80, Bethesda, MD 20892-1148, USA. Fax: +1-301-402-1370. E-mail address: ziad@nih.gov (Z.S. Saad). NeuroImage 19 (2003) 132–144 www.elsevier.com/locate/ynimg 1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8119(03)00016-8