On the nature of the BOLD f MRI contrast mechanism Nikos K. Logothetis * , Josef Pfeuffer Department Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Spemannstrasse 38, 72076 Tu ¨bingen, Germany Received 17 September 2004; accepted 15 October 2004 Abstract Since its development about 15 years ago, functional magnetic resonance imaging (fMRI) has become the leading research tool for mapping brain activity. The technique works by detecting the levels of oxygen in the blood, point by point, throughout the brain. In other words, it relies on a surrogate signal, resulting from changes in oxygenation, blood volume and flow, and does not directly measure neural activity. Although a relationship between changes in brain activity and blood flow has long been speculated, indirectly examined and suggested and surely anticipated and expected, the neural basis of the fMRI signal was only recently demonstrated directly in experiments using combined imaging and intracortical recordings. In the present paper, we discuss the results obtained from such combined experiments. We also discuss our current knowledge of the extracellularly measured signals of the neural processes that they represent and of the structural and functional neurovascular coupling, which links such processes with the hemodynamic changes that offer the surrogate signal that we use to map brain activity. We conclude by considering applications of invasive MRI, including injections of paramagnetic tracers for the study of connectivity in the living animal and simultaneous imaging and electrical microstimulation. D 2004 Elsevier Inc. All rights reserved. Keywords: Functional magnetic resonance imaging; Monkey brain; Local field potentials; Multiple-unit activity; Synaptic activity 1. Introduction Our view of brain function has improved impressively in recent years as a result of intense efforts to understand the neural mechanisms underlying perception in humans and nonhuman primates. A large body of evidence regarding the processes through which sensory information at the bio- chemical, electrophysiological and systems levels contrib- utes to the conscious experience of a stimulus has accrued. Our efforts to understand the organization and function of the sensory and perceptual systems have been greatly aided by the development of new techniques including novel and powerful methods of molecular biology, the refinement of recordings from single and multiple cells for short or long periods and noninvasive neuroimaging techniques allowing us to localize and study activity within the human brain while subjects perform a variety of cognitive tasks. The contribution of neuroimaging cannot possibly be overemphasized. All our mental capacities, ranging from sensory representation and perception to reasoning and planning, rely on distributed, synergistic activities of large neural populations; therefore, understanding these not only requires a comprehension of the physiological workings of individual neurons and glia cells but also demands a detailed map of the brain’s functional architecture, a description of the connections between populations of neurons and insights into the operations performed by the neural networks involved in the task at hand. The present review deals with spatiotemporally resolved functional magnetic resonance imaging (fMRI) in monkeys and its combination with other invasive neuroscientific techniques. Emphasis will be placed on simultaneous imaging and electrophysiology experiments aiming to elucidate the neural basis of the blood oxygen level- dependent (BOLD) signal. We first review the basic organizational principles of the cortical system. Although many examples are drawn from the visual system, generality is hardly sacrificed as evidence over the last decades suggest a similar organization in any other sensory system studied. Our intention is not to provide the reader with an exhaustive review on sensory or perceptual processing; instead, we summarize examples of current work showing the increas- ing need of neuroimaging and integrative approaches in addressing many of the interesting questions raised by 0730-725X/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mri.2004.10.018 * Corresponding author. Tel.: +49 7071 601 651; fax: +49 7071 601 652. E-mail address: nikos.logothetis@tuebingen.mpg.de (N.K. Logothetis). Magnetic Resonance Imaging 22 (2004) 1517 – 1531