Research in nonhuman primates (NHP) is technically demanding. While many NHP researchers would, in principle, like to incorporate magnetic resonance imaging into their testing, it is often challenging or impossible given constraints on scanner availability and methodological hurdles. The NIF facility at the NIH attempts to lower the barriers for imaging, thus making it feasible for anybody in the local NHP research community to obtain high resolution anatomical scans, or perform functional MRI experiments using shared equipment, coils, and methods. One of our principal functions is to make users aware of the fundamentals of fMRI, particularly when it comes to designing functional experiments. In designing research projects to understand the structure and function of the brain, researchers must understand the nature of their measurements, which in the case of MRI is best conceived as a set or series of images. A large number of steps lie between the acquisition of raw MR signals and the interpretation of neural data. This is particularly true for functional MRI (fMRI), where activity maps are generated based upon the evaluation of time varying intensity values throughout the brain from a series of MR volumes. Most neuroscience researchers are not experts in the physics or engineering aspects of MRI and thus rely heavily on experts in these domains to develop and maintain the best scanning environment possible. Thus MRI experiments are typically done in the context of a core imaging facility. In animal studies, the challenges of MRI are compounded, as technical issues such as the production of specialized radiofrequency (RF) coils and practical skills such as surgery and the animal's behavioral training become additional factors. Animal scanning is typically combined with other procedures such as pharmacological manipulation or simultaneous electrophysiological recording, often further complicating the imaging procedure. Overcoming these obstacles, however, can be of enormous value, since the capacity to map activity over the entire brain is especially powerful when combined with well-conceived manipulations or measurements. The Neurophysiology Imaging Facility (NIF) is presently organized primarily around the operation of a vertical 4.7T Bruker Biospec scanner, whose size and orientation is optimized for carrying out functional MRI experiments in seated, awake, behaving monkeys. We are presently undergoing a renovation to welcome a second scanner, in this case a 3T horizontal Siemens scanner, into the facility. This addition will provide needed additional scanning time for our users, will centralize much of the anatomical scanning, and will accommodate the needs of two newly hired principal investigators. It will also provide for a longer-term transition to replace the 4.7T vertical scanner with a cutting edge system in the future. Five staff members including Dr. Leopold, each from a different background and with different skills, aim to provide the most efficient functional scanning possible for a broad range of investigators. The main duties of the NIF staff are listed below. Structural scans: Using the standard setup, the facility staff assists with scans that aid in MRI-targeting of electrophysiological sites, identification of microelectrode positions, evaluation of experimental precision, and, importantly, the direct comparison of electrical recording sites with foci of 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 technique that relies upon particularly 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 also 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. Functional MRI scans: The most unique aspect of the facility is the capacity to conduct fMRI simultaneous with other measurements and perturbations. The Intramural Research Program at the NIH is one of the very few sites around the world in which monkeys can routinely participate in both fMRI and electrophysiological studies. The fMRI studies go beyond mapping functional specialization in the brain. Experiments within the facility typically combine fMRI with other procedures, such as microelectrode recordings or pharmacological inactivation. In the last year, neuroscience in the facility has combined fMRI with cortical ablation, pharmacological inactivation, electrocorticogram recordings, electrical microstimulation, and recordings from chronic microwire arrays. The fMRI experiments produce large data files that must be processed to evaluate the functional activity patterns across the brain. The facility provides storage of these data, as well as help in the initial processing steps. MRI Research: The NIF staff spends a relatively small fraction of its time carrying out research related to MRI itself. In the past year, we have focused on completing studies related to diffusion tractography. Dr. Frank Ye scanned several ex-vivo brain and, in a highly collaborative effort with other groups inside and outside the NIH, we recently published two papers related to the strengths and weakness of MR diffusion tractography (Thomas et al., Proc Natl Acad Sci (2014); Reveley et al., Proc Natl Acad Sci (2015)). Other research lines in the facility involve the development of scanning with newly available contrast agents. At present, the research is actively pursuing the testing of implanted radiofrequency coils, with the hope that this method can become routine for users seeking to obtain higher signal-to-noise images. Finally, in following in its ex vivo diffusion work in the macaque, the facility staff has begun to scan brains of other mammalian species to determine areas in which such scans might contribute to our understanding of brain organization through comparative studies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Scientific Cores Intramural Research (ZIC)
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Ghazizadeh, Ali; Griggs, Whitney; Leopold, David A et al. (2018) Temporal-prefrontal cortical network for discrimination of valuable objects in long-term memory. Proc Natl Acad Sci U S A 115:E2135-E2144
Seidlitz, Jakob; Sponheim, Caleb; Glen, Daniel et al. (2018) A population MRI brain template and analysis tools for the macaque. Neuroimage 170:121-131
Bogadhi, Amarender R; Bollimunta, Anil; Leopold, David A et al. (2018) Brain regions modulated during covert visual attention in the macaque. Sci Rep 8:15237
Turchi, Janita; Chang, Catie; Ye, Frank Q et al. (2018) The Basal Forebrain Regulates Global Resting-State fMRI Fluctuations. Neuron 97:940-952.e4
Liu, Xiao; de Zwart, Jacco A; Schölvinck, Marieke L et al. (2018) Subcortical evidence for a contribution of arousal to fMRI studies of brain activity. Nat Commun 9:395
Liu, Cirong; Ye, Frank Q; Yen, Cecil Chern-Chyi et al. (2018) A digital 3D atlas of the marmoset brain based on multi-modal MRI. Neuroimage 169:106-116
Takemura, Hiromasa; Pestilli, Franco; Weiner, Kevin S et al. (2017) Occipital White Matter Tracts in Human and Macaque. Cereb Cortex 27:3346-3359
Reveley, Colin; Gruslys, Audrunas; Ye, Frank Q et al. (2017) Three-Dimensional Digital Template Atlas of the Macaque Brain. Cereb Cortex 27:4463-4477
Papoti, Daniel; Yen, Cecil Chern-Chyi; Hung, Chia-Chun et al. (2017) Design and implementation of embedded 8-channel receive-only arrays for whole-brain MRI and fMRI of conscious awake marmosets. Magn Reson Med 78:387-398
Chang, Catie; Leopold, David A; Schölvinck, Marieke Louise et al. (2016) Tracking brain arousal fluctuations with fMRI. Proc Natl Acad Sci U S A 113:4518-23

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