Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. Seventy-two adult (male) rats were randomly assigned to one of three conditions (skilled reaching, unskilled reaching, and caged control). After 11 d of training, postmortem diffusion MRI revealed significantly higher FA in the skilled reaching group compared with the control groups, specifically in the WM subjacent to the sensorimotor cortex contralateral to the trained limb. In addition, within the skilled reaching group, FA across widespread regions of WM in the contralateral hemisphere correlated significantly with learning rate. Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.

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Comparing the brains of related species faces the challenges of establishing homologies whilst accommodating evolutionary specializations. Here we propose a general framework for understanding similarities and differences between the brains of primates. The approach uses white matter blueprints of the whole cortex based on a set of white matter tracts that can be anatomically matched across species. The blueprints provide a common reference space that allows us to navigate between brains of different species, identify homologous cortical areas, or to transform whole cortical maps from one species to the other. Specializations are cast within this framework as deviations between the species’ blueprints. We illustrate how this approach can be used to compare human and macaque brains.

Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10 5 cells) than those volumes detectable clinically (10 7 -10 8 cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.

Evolutionary adaptations of the human brain are the basis for our unique abilities such as language. An expansion of the arcuate fasciculus (AF), the dorsal language tract, in the human lineage involving left lateralization is considered canonical, but this hypothesis has not been tested in relation to other architectural adaptations in the human brain. Using diffusion-weighted MRI, we examined AF in the human and macaque and quantified species differences in white matter architecture and surface representations. To compare surface results in the two species, we transformed macaque representations to human space using a landmark-based monkey-to-human cortical expansion model. We found that the human dorsal AF, but not the ventral inferior fronto-occipital fasciculus (IFO), is left-lateralized. In the monkey AF is not lateralized. Moreover, compared to the macaque, human AF is relatively increased with respect to IFO. A comparison of human and transformed macaque surface representations suggests that cortical expansion alone cannot account for the species differences in the surface representation of AF. Our results show that the human AF has undergone critical anatomical modifications in comparison with the macaque AF. More generally, this work demonstrates that studies on the human brain specializations underlying the language connectome can benefit from current methodological advances in comparative neuroanatomy.

Amide Proton Transfer (APT) reports on contrast derived from the exchange of protons between amide groups and water. Commonly, APT contrast is quantified by asymmetry analysis, providing an ensemble contrast of both amide proton concentration and exchange rate. An alternative is to sample the off-resonant spectrum and fit an exchange model, permitting the APT effect to be quantified, correcting automatically for confounding effects of spillover, field inhomogeneity, and magnetization transfer. Additionally, it should permit amide concentration and exchange rate to be independently quantified. Here, a Bayesian method is applied to this problem allowing pertinent prior information to be specified. A three-pool model was used incorporating water protons, amide protons, and magnetization transfer effect. The method is demonstrated in simulations, creatine phantoms with varying pH and in vivo (n = 7). The Bayesian model-based approach was able to quantify the APT effect accurately (root-mean-square error < 2%) even when subject to confounding field variation and magnetization transfer effect, unlike traditional asymmetry analysis. The in vivo results gave approximate APT concentration (relative to water) and exchange rate values of 3 × 10(-3) and 15 s(-1) . A degree of correlation was observed between these parameter making the latter difficult to quantify with absolute accuracy, suggesting that more optimal sampling strategies might be required.

We compared the course and cortical projections of white matter fibers passing through the extreme capsule in humans and macaques. Previous comparisons of this tract have suggested a uniquely human posterior projection, but these studies have always employed different techniques in the different species. Here we used the same technique, diffusion MRI, in both species to avoid attributing differences in techniques to differences in species. Diffusion MRI-based probabilistic tractography was performed from a seed area in the extreme capsule in both human and macaques. We compared in vivo data of humans and macaques as well as one high-resolution ex vivo macaque dataset. Tractography in the macaque was able to replicate most results known from macaque tracer studies, including selective innervation of frontal cortical areas and targets in the superior temporal cortex. In addition, however, we also observed some tracts that are not commonly reported in macaque tracer studies and that are more reminiscent of results previously only reported in the human. In humans, we show that the ventrolateral prefrontal cortex innervations are broadly similar to those in the macaque. These results suggest that evolutionary changes in the human extreme capsule fiber complex are likely more gradual than punctuated. Further, they demonstrate both the potential and limitations of diffusion MRI tractography.

The interactions of anterior temporal structures, and especially the amygdala, with the prefrontal cortex are pivotal to learning, decision-making, and socio-emotional regulation. A clear anatomical description of the organization and dissociation of fiber bundles linking anterior temporal cortex/amygdala and prefrontal cortex in humans is still lacking. Using diffusion imaging techniques, we reconstructed fiber bundles between these anatomical regions in human and macaque brains. First, by studying macaques, we assessed which aspects of connectivity known from tracer studies could be identified with diffusion imaging. Second, by comparing diffusion imaging results in humans and macaques, we estimated the patterns of fibers coursing between human amygdala and prefrontal cortex and compared them with those in the monkey. In posterior prefrontal cortex, we observed a prominent and well-preserved bifurcation of bundles into primarily two fiber systems—an amygdalofugal path and an uncinate path—in both species. This dissociation fades away in more rostral prefrontal regions.