Spatial relationship between neuronal activity and BOLD functional MRI

Abstract

Despite the ubiquitous use of functional magnetic resonance imaging (fMRI), the extent to which the magnitude and spatial scale of the fMRI signal correlates with neuronal activity is poorly understood. In this study, we directly compared single and multiunit neuronal activity with blood oxygenation level-dependent (BOLD) fMRI responses across a large area of the cat area 18. Our data suggest that at the scale of several millimeters, the BOLD contrast correlates linearly with the underlying neuronal activity. At the level of individual electrode recording sites, however, the correlation between the two signals varied substantially. We conclude from our study that T₂*-based positive BOLD signals are a robust predictor for neuronal activity only at supra-millimeter spatial scales.

Introduction

Since its introduction in 1992 Bandettini et al., 1992, Kwong et al., 1992, Ogawa et al., 1992 blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has revolutionized cognitive neurosciences by allowing the foci of cortical “activity” to be visualized in vivo in a noninvasive manner. The BOLD contrast originates from the intravoxel magnetic field inhomogeneity induced by paramagnetic deoxyhemoglobin (deoxyHb) sequestered in red blood cells that are compartmentalized within blood vessels. The magnetic susceptibility differences between the deoxyHb-containing compartments and the surrounding space generate magnetic field gradients around the boundaries of these compartments. Therefore, perturbation of regional deoxyHb content will alter the signal intensities in MR images sensitized to BOLD contrast. Such regional perturbation occurs as the result of enhanced neuronal activity and metabolism during sensory (Engel et al., 1994), motor (Kim et al., 1993), or cognitive (Wagner et al., 1998) functions.

While BOLD-based neuroimaging studies have provided unprecedented amount of insights into the workings of the human brain in vivo, the explanatory power of BOLD fMRI is currently limited since there is a fundamental gap in our understanding of the linkage between the observed BOLD contrast and the underlying neuronal physiology. In particular, the extent to which the magnitude and spatial scale of the BOLD signal correlates with neuronal physiology remains elusive Attwell and Iadecola, 2002, Ugurbil et al., 2003 To this end, a growing body of results suggests a predominantly linear coupling between BOLD and neuronal activity. For example, a recent study by Ogawa et al. (2000) demonstrated a linear relationship between somatosensory-evoked potentials and BOLD signals for brief stimulation durations. Rees et al. (2000) and Heeger et al. (2000) demonstrated a linear correlation between BOLD contrast in humans and averaged spike rate in a monkey cortical area during stimulation with nearly identical stimuli. A similarly linear relationship was observed also in anesthetized monkeys by Logothetis et al. (2001), a study in which single-unit responses were acquired simultaneously with BOLD signals inside the MRI scanner.

While the above results suggest that the fundamental coupling between BOLD and the underlying neuronal activity is approximately linear, important questions remain about the spatial scale over which the linear coupling remains valid. Is the hypothesized linear coupling between BOLD and neuronal activity invariant across the different spatial scales of the cortical architecture? Can we assume a universal linearity from the spatial scale of entire cortical areas (several millimeters to centimeters) to individual cortical columns (sub-millimeter)? Such universal linearity would be surprising, since the BOLD signal is not a direct measure of neuronal activity per se. Rather, it is a complex convolution of changes in cerebral metabolic rate of oxygen (CMRO₂), cerebral blood flow (CBF), and cerebral blood volume (CBV) following focal neuronal activity. Therefore, spatial specificity of BOLD response becomes a critical issue in examining its relationship to the underlying neuronal activity. It is in principle possible to record from a site where neuronal activity is absent but there exists a large BOLD response as the latter effect “spills over” from an adjacent active region due to lack of spatial specificity. Consequently, it cannot be assumed a priori that the correlation between the BOLD signals and the underlying neural activity is linear irrespective of spatial considerations, especially at the sub-millimeter scale at which the finest details of spatial organization in cortex have been observed.

In the present study, we utilize a novel recording scheme to characterize the relationship between BOLD fMRI signals and the underlying neuronal modulation within the same animals from multiple electrode recording sites over a large cortical area. Our study extends recent results (Logothetis et al., 2001) in which correlations between BOLD and neuronal activity were characterized from a single electrode penetration site. With multiple recording sites spaced over the entire cat area 18 on the lateral gyrus, the results of our study provide a detailed look into the spatial relationship between neuronal activity and BOLD functional signals.