Sean Foxley

Motor skill learning induces changes in white matter microstructure and myelination.

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.

Detecting microstructural properties of white matter based on compartmentalization of magnetic susceptibility.

The microscopic structure of neuronal tissue is crucial to brain function, with axon diameter, axonal density and myelination directly influencing signal conduction in the white matter. There is increasing evidence that these microstructural properties alter signal in magnetic resonance imaging (MRI) driven by magnetic susceptibility of different compartments (e.g., myelin sheaths and iron-laden cells). To explain these observations, we have developed a multi-compartmental geometric model of whitematter microstructure. Using a single set of literature parameters, this forward model predicts experimentally observed orientation dependence and temporal evolution of the MRI signal. Where previous models have aimed to explain only the orientation dependence of signal phase, the proposed approach encapsulates the full repertoire of signal behavior. The frequency distribution underlying signal behavior is predicted to be a rich source of microstructural information with relevance to neuronal pathology.

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought.

Sensitivity to tumor microvasculature without contrast agents in high spectral and spatial resolution MR images

Contrast‐enhanced (CE)‐MRI is sensitive to cancers but can produce adverse reactions and suffers from insufficient specificity and morphological detail. This research investigated whether high spectral and spatial resolution (HiSS) MRI detects tumor vasculature without contrast agents, based on the sensitivity of the water resonance line shape to tumor blood vessels. HiSS data from AT6.1 tumors inoculated in the hind legs of rats (N = 8) were collected pre‐ and post–blood pool contrast agent (iron‐oxide particles) injection. The waterline in small voxels was significantly more asymmetric at the tumor rim compared to the tumor center and normal muscle (P < 0.003). Composite images were synthesized, with the intensity in each voxel determined by the Fourier component (FC) of the water resonance having the greatest relative image contrast at that position. We tested whether regions with high contrast in FC images (FCIs) contain vasculature by comparing FCIs with CE‐MRI as the “gold standard” of vascular density. The FCIs had 75% ± 13% sensitivity, 74% ± 10% specificity, and 91% ± 4% positive predictive value (PPV) for vasculature detection at the tumor rim. These results suggest that tumor microvasculature can be detected using HiSS imaging without the use of contrast agents. Magn Reson Med 61:291–298, 2009.

Fat suppression with spectrally selective inversion vs. high spectral and spatial resolution MRI of breast lesions: Qualitative and quantitative comparisons

To compare conventional fat‐suppressed MR images of the breast to images derived from high spectral and spatial resolution MR data. Image quality and the level of fat suppression are compared qualitatively and quantitatively.

Improving diffusion-weighted imaging of post-mortem human brains: SSFP at 7 T.

Post-mortem diffusion imaging of whole, human brains has potential to provide data for validation or high-resolution anatomical investigations. Previous work has demonstrated improvements in data acquired with diffusion-weighted steady-state free precession (DW-SSFP) compared with conventional diffusion-weighted spin echo at 3 T. This is due to the ability of DW-SSFP to overcome signal-to-noise and diffusion contrast losses brought about by tissue fixation related decreases in T2 and ADC. In this work, data of four post-mortem human brains were acquired at 3 T and 7 T, using DW-SSFP with similar effective b-values (beff ~ 5150 s/mm2) for inter-field strength comparisons; in addition, DW-SSFP data were acquired at 7 T with higher beff (~ 8550 s/mm2) for intra-field strength comparisons. Results demonstrate that both datasets acquired at 7 T had higher SNR and diffusion contrast than data acquired at 3 T, and data acquired at higher beff had improved diffusion contrast than at lower beff at 7 T. These results translate to improved estimates of secondary fiber orientations leading to higher fidelity tractography results compared with data acquired at 3 T. Specifically, tractography streamlines of cortical projections originating from the corpus callosum, corticospinal tract, and superior longitudinal fasciculus were more successful at crossing the centrum semiovale and projected closer to the cortex. Results suggest that DW-SSFP at 7 T is a preferential method for acquiring diffusion-weighted data of post-mortem human brain, specifically where the primary region of interest involves crossing white matter tracts.

Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction

Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain–Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure–function correlations in patients with cerebellar disorders using tractography of the DRTT.

Curcumin aggravates CNS pathology in experimental systemic lupus erythematosus.

Complement activation and inflammation are key disease features of systemic lupus erythematosus. Curcumin is an anti-inflammatory agent that inhibits the complement cascade. Therefore, we hypothesized that curcumin will be protective in CNS lupus. To assess the effect of curcumin on CNS-lupus, MRL/lpr mice were used. Brain MRI showed that curcumin (30mg/kg body wt. i.p. from 12-20 weeks) worsened regional brain atrophy. The volumes of the lateral and third ventricles are significantly increased (150%-213% and 107%-140%, without and with treatment respectively compared to MRL+/+ controls). The hippocampus was reduced further (83%-81%) by curcumin treatment. In line with increased brain atrophy, there were edematous cells (41% increase in cell size in MRL/lpr compared to MRL+/+ mice. The cell size was further increased by 28% when treated with curcumin; p<0.02) in the cortex. In line with increased atrophy and edema, there was a significant increase (p<0.02) in the mRNA and protein expression of the water channel protein, aquaporin 4 in these mice. The increase in the matrix proteins, glial fibrillary acidic protein and vimentin in lupus mice in the hippocampus was prevented by curcumin. Curcumin increased IgG deposits and decreased C3 deposits in brain with a corresponding increase in immune complexes and decrease in C3 concentration (by 60% in MRL/lpr mice Vs. MRL+/+ mice and a further 26% decrease when treated with curcumin) in circulation. Decrease in C3 could alter the transport of immune complexes leading to an increase in IgG deposits which could induce inflammatory pathways thereby leading to worsening of the disease. The neurological outcome as measured by maze performance indicates that the curcumin treated mice performed poorly compared to the untreated counterparts. Our results for the first time provide evidence that at the dose used in this study, curcumin aggravates some CNS disease manifestations in experimental lupus brain. Therefore, until a safe dose range is established by additional studies, and the validity of the findings is determined in human patients, caution may be warranted in the use of curcumin, even as adjuvant therapy for CNS lupus.

High spectral and spatial resolution MRI of age related changes in murine prostate

The purpose of this work was to evaluate high‐resolution echo‐planar spectroscopic MRI of normal and precancerous prostatic changes in a transgenic mouse line. Simian virus large T‐antigen transgenic male mice (N = 7, age = 34 ± 3.7 weeks) with prostatic hyperplasia and intraepithelial neoplasia (PIN) were studied. High spectral and spatial resolution (HiSS) MRI of the water proton signal was compared to the free induction decay (FID) integral image and conventional gradient‐echo and spin‐echo imaging. Water peak‐height images of the prostate produced from HiSS datasets showed improved contrast‐to‐noise ratio (CNR) (P < 0.03), and greater morphological detail (P < 0.004) based on texture analysis. Despite the high spectral resolution of the HiSS datasets, signal‐to‐noise ratio (SNR) compared favorably with that of the FID integral and conventional images. Lobular features in HiSS images of older mice were consistent with hyperplasia seen on histology. A partially deuterated water‐filled catheter was inserted in the mouse rectum for susceptibility matching between the colon interior and exterior to minimize image artifacts. These preliminary results suggest that HiSS MRI provides detailed morphology of the murine prostate and can detect early changes associated with the development of cancer. HiSS MRI of patients may have similar advantages. Magn Reson Med 60:575–581, 2008.

The effect of realistic geometries on the susceptibility-weighted MR signal in white matter.

To investigate the effect of realistic microstructural geometry on the susceptibility‐weighted MR signal in white matter (WM), with application to demyelination.