Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T 1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn 2þ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn 2þ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn 2þ to the target areas of interest.

Development of efficient imaging techniques to trace neuronal connections would be very useful. Manganese ion (Mn2+) is an excellent T1 contrast agent for magnetic resonance imaging (MRI). Four reports utilizing radioactive Mn2+ in fish and rat brain indicate that Mn2+ may be useful for tracing neuronal connections. Therefore, the purpose of this work was to determine if Mn2+ can be used as an in vivo MRI neuronal tract tracer. The results indicate that topical administration of MnCI2 solution to the naris of mice as well as to the retinal ganglion cells via intravitreal injection leads to enhancement of contrast along the respective pathways. Therefore, application of Mn2+ to neurons allows the use of MRI to visualize neuronal connections.

In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure-function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately. diffusion MRI | tractography | neuroanatomy | white matter | connectome T he primate cerebral cortex consists of dozens of areas distinguished by their cytoarchitectonic profiles (1), sensory maps (2), functional specialization (3), and spontaneous activity covariation (4). Attention within neuroscience has increasingly focused on understanding how connectivity among these regions underpins brain function in health and in disease (5). The macaque monkey (Macaca mulatta) has been a fruitful neuroscientific model because the functional organization of its brain is similar in many ways to that of the human (6-8). Tracer injections in the macaque have revealed that virtually all cortical areas give rise to long-range connections, many of which project to other cortical areas, potentially to form processing hierarchies (9). This understanding continues to shape views of functional organization in the human brain. However, studying long-range connections through tracer injections is time consuming, inefficient, and prone to sampling biases, because a given experiment can measure connectivity to only one or a small number of cortical sites. Moreover, although in many respects the macaque brain is a good approximation of the human brain, both species have undergone profound evolutionary changes since the time of their most recent...

MRI at high field can be sensitized to the magnetic properties of tissues, which introduces a signal dependence on the orientation of white matter (WM) fiber bundles relative to the magnetic field. In addition, study of the NMR relaxation properties of this signal has indicated contributions from compartmentalized water environments inside and outside the myelin sheath that may be separable. Here we further investigated the effects of water compartmentalization on the MRI signal with the goal of extracting compartment-specific information. By comparing MRI measurements of human and marmoset brain at 7 T with magnetic field modeling, we show that: (1) water between the myelin lipid bilayers, in the axonal, and in the interstitial space each experience characteristic magnetic field effects that depend on fiber orientation (2) these field effects result in characteristic relaxation properties and frequency shifts for these compartments; and (3) compartmental contributions may be separated by multi-component fitting of the MRI signal relaxation (i.e. decay) curve. We further show the potential application of these findings to the direct mapping of myelin content and assessment of WM fiber integrity with high field MRI.