Two and a half decades ago, visualizing structures in the brain was limited to surgery and suboptimal imaging techniques such as x-ray. Since that time, there have been continual advancements in brain imaging, with the most impressive methods centered upon MRI. MRI, which essentially visualizes the quantum properties of water molecules in different tissues, suddenly made it possible to visualize and study the body, including the brain, in three dimensions. In neuroscience, MRI additionally provides a means to visualize functional activity rooted in the communication of neurons. Functional MR imaging, commonly known as fMRI, is a noninvasive tool used by investigators in nearly every university, and in many countries around the world. It is commonly used to measure and assess various aspects of brain function in humans, such as the neural basis of perception, action, reward, and decision-making. As such, this technology changed the way in which researchers view the field of neuroscience, and to some extent the way in which the public views the brain. For all its positive qualities, fMRI has certain shortcomings that limit its capacity for investigating electrical processes in the brain. For example, compared to invasive neurophysiological techniques, fMRI is coarse and approximate. Its window into the physiology of the brain is limited by its spatial resolution (millimeters) and temporal resolution (seconds), which are inadequate to study microscopic processes happening at millisecond time scales. Even more importantly, fMRI does not measure neural activity directly, but instead measures regional change in the perfusion of tissue with blood that accompanies changes in brain activity. For this reason, understanding how blood flow is coupled with neural activity becomes a critical, and vexing, question in systems neuroscience. The Neurophysiology Imaging Facility (NIF) is a centralized core facility bringing together a broad range of electrophysiology research and imaging in nonhuman primates in an effort to provide the most integrated and efficient glimpses into the brain. Investigators in each of the three sponsoring institutes (NIMH, NINDS, and NEI) have the opportunity to image the structure and function of the nonhuman primate brain, exploiting the latest in cutting-edge imaging technology. Projects in the facility vary in their specifics, but generally aim to combine imaging with other invasive techniques, such as microelectrode recordings, pharmacological inactivation, or anatomical tract tracing. Of course, testing animals inside a strong magnetic field poses particular challenges. In order to bring the program to a functional state, we developed a wide array of MRI-compatible equipment, including animal chairs, restraint devices, reward delivery apparatus, eye position tracking cameras, and manual response keys. This development has allowed for the systematic imaging of many nonhuman primates in the facility, and has created a unique situation at NIH, where electrophysiology studies and imaging can be fluidly combined in a way that does not require fundamentally different preparations. Using the standard setup, we are able to do routine MRI-targeting of electrophysiological sites, microelectrode recordings, evaluation of experimental precision, and, importantly, the direct comparison of electrical with fMRI responses in the context of a cognitive task. We are further able to combine these techniques with (1) reversible inactivation of electrical neural activity using pharmacological agents, (2) the identification of anatomical pathways using transported, MRI-visible chemicals such as manganese chloride, and (3) electrical microstimulation, where small local currents activate neurons that project to regions that can be detected using the fMRI signal. Surgical targeting is another main objective for high-resolution scanning in the NIF core facility. This relies upon high-quality, distortion-free 3-D images of the brain. We have recently implemented algorithms that measure and compensate for small geometric distortions in the images that might hamper surgical precision. The facility offers a frameless stereotaxy protocol to assist the surgeon with implantation. This method permits a visualization of the high-resolution scan during surgery, with a real-time depiction of the surgical instruments relative to the scanned brain structures. We have used this approach routinely to aid in the accurate implantation of electrode bundles and chronic cannulae, targeted ablations, and the placement of recording chambers.
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