A great advancement in medicine has been the use of magnetic resonance (MR) imaging to visualize tissue in great detail, and in three dimensions, inside the body. In no field has imaging impacted biomedical research more than in the study of the brain, for which MR allows one to visualize not only its structure, but also its function. 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 brain research. Like all emergent technologies, fMRI is founded on assumptions and approximations, and cannot replace other experimental techniques. For example, its window into the physiology of the brain is limited by its spatial resolution (millimeters) and its temporal resolution (seconds), which are inadequate to study microscopic processes happening at millisecond time scales. Importantly, fMRI does not measure neural activity directly, but instead measures regional changes in the perfusion of tissue with blood that accompanies changes in brain activity. For these reasons, understanding how changes in blood flow are coupled with increases and decreases neural activity becomes a critical, and vexing, question for systems neuroscience research. Work in experimental animals remains a vital part of the investigation of the brain, including the nature of the fMRI signal. Historically, most advancements in understanding the human brain have arisen from the careful examination of neural activity in the brains of animals, and in particular of nonhuman primates. 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 brain physiology. In the contextt of the NIF core, 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. One main objective in the NIF core has been to create a viable and efficient means by which monkeys enrolled in a regimen of electrophysiological testing can also be tested using fMRI. This goal was achieved only after considerable development. For example, the equipment involved in training and testing the animal, such as animal chairs, restraint devices, reward delivery apparatus, eye position tracking cameras, and manual response keys, were all modified so that they worked inside the strong magnetic field of the MR scanner. Overcoming these hurdles was important, since now the animals can be tested on alternate days in either the neurophysiology or MRI environment -- two testing situations with very different constraints. This possibility has created a unique environment at the NIH, where electrophysiology studies and imaging can be fluidly combined in a way that does not require two fundamentally different preparations. The single preparation can be used for MR-targeting of electrophysiological recording sites, execution of the electrophysiological recordings themselves, evaluation of experimental precision of the recordings, and, importantly, the direct comparison of electrical with functional MRI responses in the context of a cognitive task. Beyond studying the basis of the fMRI signal, the combination of invasive and imaging approaches allows experimental questions to be advanced that would otherwise be intractable: (1) For example, we routinely combine neuropharmacology with imaging. In contrast to purely correlative studies, in which the responses of the brain are compared with a cognitive variable, the local injection of pharmacological agents allows one to test more specific hypotheses by perturbing sensory or cognitive circuits. For example, by locally inactivating one nucleus or cortical region of the brain with the injection of the GABA agonist muscimol, we have been able to examine the effects of fMRI activity in other brain regions. This novel approach has permitted unprecedented visualization of how one small area of the brain affects activity over the entire brain. (2) Recent advancements in track-tracing make it possible to study the anatomical connectivity of the brain by injecting microliter quantities of manganese chloride. This chemical is taken up by individual neurons and transported to areas to which those neurons project. It also has the fortuitous property of being visible on MR scans, showing up as bright white against the gray background. This technique permits the visualization of anatomical connections in the brain of intact animals, an impossibility until just a few years ago. (3) To study the link between the fMRI signal and the underlying electrical activity, we have also developed the capacity for simultaneous microelectrode recordings in the scanner. This is achieved using implanted multicontact electrodes, allowing for the study of the relationship of the two signals during both stimulus-based and spontaneous activity. (4) Electrical microstimulation is one of the oldest neurophysiological tools. Inside the scanner, small electrical currents combined with the monitoring of activity elsewhere, provides insights into the circuitry underlying both sensory and motor responses in the brain. Finally, a main goal of the NIF core facility is to provide high-resolution structural imaging for the wide NIH user community. Work in the facility has involved the optimization of high-resolution scans, including the minimization of geometrical distortions caused by inevitable inhomogeneities in the magnetic field. The precise targeting and evaluation of recording sites is routinely carried out in both the awake and fully anesthetized animal preparation. In addition, the facility offers a number of techniques to electrophysiologists in order to facilitate targeted microelectrode recordings. For example, a frameless stereotaxy system permits surgical approach to any target from any angle, allowing for a complete evaluation of potential trajectories of interest, as well as structures to be avoided. This approach is used regularly by users of the facility, and has contributed to the highly reliable targeting of deep cortical and subcortical structures.
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