Appl. Magn. Reson. 28, 1XXX (2005) Applied Magnetic Resonance © Springer-Verlag 2005 Printed in Austria Direct Detection of Neuronal Activity with MRI: Fantasy, Possibility, or Reality? P. A. Bandettini 1,2 , N. Petridou 1 , and J. Bodurka 2 1 Unit on Functional Imaging Methods, Laboratory of Brain and Cognition and 2 Functional MRI Facility, National Institute of Mental Health, National Institutes of Health, Bethesola, Maryland, USA Received November 29, 2004; revised January 7, 2005 Abstract. Hemodynamic-based functional magnetic resonance imaging (fMRI) techniques have proven to be extremely robust and sensitive methods for noninvasive detection and mapping of human brain activation. Nevertheless, limitations in temporal and spatial resolution as well as interpretation re- main because hemodynamic changes accompanying brain activation are relatively sluggish and vari- able, and therefore imprecise measures of neuronal activity. A hope among brain imagers would be to possess a technique that would allow direct mapping of brain activity with spatial resolution on the order of a cortical column and temporal resolution on the order of an action potential or at least a post synaptic potential. Recent efforts in understanding the direct effects of neuronal activity on MRI signal have provided some degree of hope for those who want a more precise noninvasive brain activation mapping technique than fMRI as we know it now. While the manner in which electrical currents influence MRI signal is well understood, the manner in which neuronal firing spatially and temporally integrates on the spatial scale of an MRI voxel to produce a magnetic field shift and subsequently a NMR phase and/or magnitude change is not well understood. It is also not estab- lished that this field shift would be large or long enough in duration to be detected. The objective of this paper is to provide a perspective of the work that has been performed towards the direction of achieving direct neuronal current imaging with MRI. A specific goal is to further clarify what is understood about the theoretical and practical possibilities of neuronal current imaging. Specifically discussed are modeling efforts, phantom studies, in vitro studies, and human studies. 1 Introduction The type of questions that researchers can ask regarding the functional organiza- tion of the human brain are tightly intertwined with the technology and methods at their disposal. In the past decade, the development of functional magnetic reso- nance imaging (fMRI) has precipitated an explosion of effort, and new findings because its ease of implementation, temporal and spatial resolution, and sensitiv- ity. While applications for and sophistication of fMRI continues to grow, researchers are daily confronted with its limitations in temporal and spatial resolution, sensi-