In vivo manganese tract tracing of frontal eye fields in rhesus macaques with ultra-high field MRI: Comparison with DWI tractography

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The saccadic eye movement system has emerged as a valuable model for studying neural circuitry related to flexible control of behavior. Although connections of the saccadic circuitry are well documented via histochemical tracers, these methods require fixed tissue and thus cannot provide longitudinal assessments of connectivity. To circumvent this, diffusion weighted imaging (DWI) is often used as a proxy for connectivity in vivo, allowing for the tracing of connections longitudinally and noninvasively. DWI, however, has certain limitations in its ability to estimate the paths of fiber tracts. Here, we demonstrate the use of manganese, in an animal model, as an MRI-based in vivo labeling technique for saccadic circuitry that allows for direct tract tracing without the need to sacrifice the animal. Manganese is a strong paramagnetic contrast agent used for T1-relaxation enhancement in MRI. Here, we locally injected MnCl into the frontal eye fields (FEF), a key saccadic node, of two male rhesus macaques and collected ultra-high field MRI data at 7 T (T1, DWI). The results demonstrate that MnCl-traced FEF connections parallel those established by histochemical tracing (albeit at a lower spatial resolution) and suggest that DWI underestimates FEF connectivity, likely due to crossing fibers and small tract size. These results highlight the lack of DWI sensitivity for tracing subcortical FEF fibers, but also suggest MnCl-based tracing as a powerful alternative for assessing these connections in vivo.