Faculty Bibliography

Chromium (Cr) has been used histologically to stabilize lipid fractions in the retina and is suggested to enhance oxidizable lipids in brain MRI. This study explored the feasibility, sensitivity, and specificity of in vivo chromium-enhanced MRI of retinal lipids by determining its spatiotemporal profiles and toxic effect after intravitreal Cr(VI) injection to normal adult rats. One day after 3 muL Cr(VI) administration at 1-100 mM, the retina exhibited a dose-dependent increase in T1-weighted hyperintensity until 50 mM. Time-dependently, significant T1-weighted hyperintensity persisted up to 2 weeks after 10 mM Cr(VI) administration. Three-dimensional chromium-enhanced MRI of ex vivo normal eyes at isotropic 50-mum resolution showed at least five alternating bands across retinal layers, with the outermost layer being the brightest. This agreed with histology indicating alternating lipid contents with the highest level in the photoreceptor layer of the outer retina. Although Cr(VI) reduction may induce oxidative stress and depolymerize microtubules, manganese-enhanced MRI after chromium-enhanced MRI showed a dose-dependent effect of Cr toxicity on manganese uptake and axonal transport along the visual pathway. These results potentiated future longitudinal chromium-enhanced MRI studies on retinal lipid metabolism upon further optimization of Cr doses with visual cell viability.

Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.

Tonotopy, the topographic encoding of sound frequency, is the fundamental property of the auditory system. Invasive techniques lack the spatial coverage or frequency resolution to rigorously investigate tonotopy. Conventional auditory fMRI is corrupted by significant image distortion, sporadic acoustic noise and inadequate frequency resolution. We developed an efficient and high fidelity auditory fMRI method that integrates continuous frequency sweeping stimulus, distortion free MRI sequence with stable scanner noise and Fourier analysis. We demonstrated this swept source imaging (SSI) in the rat inferior colliculus and obtained tonotopic maps with ~2 kHz resolution and 40 kHz bandwidth. The results were vastly superior to those obtained by conventional fMRI mapping approach and in excellent agreement with invasive findings. We applied SSI to examine tonotopic injury following developmental noise exposure and observed that the tonotopic organization was significantly disrupted. With SSI, we also observed the subtle effects of sound pressure level on tonotopic maps, reflecting the complex neuronal responses associated with asymmetric tuning curves. This in vivo and noninvasive technique will greatly facilitate future investigation of tonotopic plasticity and disorders and auditory information processing. SSI can also be adapted to study topographic organization in other sensory systems such as retinotopy and somatotopy.

Quantitative diffusion tensor imaging (DTI) offers a valuable tool to probe the microstructural changes in neural tissues in vivo, where absolute quantitation accuracy and reproducibility are essential. It has been long recognized that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced by the presence of water molecules in cerebrovasculature. However, little is known about to what extent such blood signal affects DTI quantitation. In this study, we quantitatively examined the effect of cerebral hemodynamic change on DTI indices by using a standard multislice echo planar imaging (EPI) spin echo (SE) DTI acquisition protocol and a rat model of hypercapnia. In response to 5% CO(2) challenge, mean, radial and axial diffusivities measured with diffusion factor (b-value) of b=1.0 ms/mum(2) were found to increase in whole brain (1.52%+/-0.22%, 1.66%+/-0.16% and 1.35%+/-0.37%, respectively), gray matter (1.56%+/-0.23%, 1.63%+/-0.14% and 1.47%+/-0.45%, respectively) and white matter regions (1.45%+/-0.28%, 1.88%+/-0.33% and 1.10%+/-0.26%, respectively). Fractional anisotropy (FA) was found to decrease by 1.67%+/-0.38%, 1.91%+/-0.59% and 1.46%+/-0.30% in whole brain, gray matter and white matter regions, respectively. In addition, these diffusivity increases and FA decreases became more pronounced at a lower b-value (b=0.3 ms/mum(2)). The results indicated that in vivo DTI quantitation in brain can be contaminated by vascular factors on the order of few percentages. Consequently, alterations in cerebrovasculature and hemodynamics can affect the DTI quantitation and its efficacy in characterizing the neural tissue microstructures in normal and diseased states. Caution should be taken in designing and interpreting quantitative DTI studies as all DTI indices can be potentially confounded by physiologic conditions and by cerebrovascular and hemodynamic characteristics.

The aim of this study is to employ tract-based spatial statistics (TBSS) to analyze the voxel-wise differences in DTI parameters between normal and mild hypoxic-ischemic (HI) neonatal brains. Forty-one full term neonates (24 normal controls and 17 with mild HI injury) and 31 preterm neonates (20 normal controls and 11 with mild HI injury) underwent T1 weighted imaging, T2 weighted imaging and diffusion tensor imaging (DTI) within 28 days after birth. The voxel differences of fractional anisotropy (FA), lambda1, lambda2, and lambda3 values between mild HI group and control group were analyzed in preterm and full term neonates respectively. The significantly decreased FA with increased lambda2, lambda3 in corticospinal tract, genu of corpus callosum (GCC), external capsule (EC) and splenium of the corpus callosum (SCC) in mild HI neonates suggested deficits or delays in both myelination and premyelination. Such impaired corticospinal tract, in both preterm and term neonates, may directly lead to the subsequent poor motor performance. Impaired EC and SCC, the additional injured sites observed in full term neonates with mild HI injury, may be causally responsible for the dysfunction in coordination and integration. In conclusion, TBSS provides an objective, independent and sensitive method for DTI data analysis of neonatal white matter alterations after mild HI injury.

Diffusion kurtosis imaging (DKI), an extension of diffusion tensor imaging (DTI), provides a practical method to describe non-Gaussian water diffusion in neural tissues. The sensitivity of DKI to detect the subtle changes in several chosen brain structures has been studied. However, intuitive and holistic methods to validate the merits of DKI remain to be explored. In this paper, tract-based spatial statistics (TBSS) was used to demonstrate white matter alterations in both DKI and DTI parameters in preschool children (1-6 years; n=10). Correlation analysis was also performed in multiple regions of interest (ROIs). Fractional anisotropy, mean kurtosis, axial kurtosis and radial kurtosis increased with age, while mean diffusivity and radial diffusivity decreased significantly with age. Fractional anisotropy of kurtosis and axial diffusivity were found to be less sensitive to the changes with age. These preliminary findings indicated that TBSS could be used to detect subtle changes of DKI parameters on the white matter tract. Kurtosis parameters, except fractional anisotropy of kurtosis, demonstrated higher sensitivity than DTI parameters. TBSS may be a convenient method to yield higher sensitivity of DKI.

The superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, whose superficial layers receive visual information from the retina in a topological order. Despite the increasing number of studies investigating retinotopic projection in visual brain development and disorders, in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei has not yet been available. This study explores the capability of 3D manganese-enhanced MRI (MEMRI) at 200 mum isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn(2+) injection into both eyes, animals with partial transection at the right superior intraorbital optic nerve in Group 1 (n=8) exhibited a significantly lower T1-weighted signal intensity in the lateral region of the left SC compared to the left medial SC and right control SC. Partial transection toward the temporal or nasal region of the right intraorbital optic nerve in Group 2 (n=7) led to T1-weighted hypointensity in the rostral or caudal region of the left SC, whereas a clear border was observed separating 2 halves of the left SC in all groups. Previous histological and electrophysiological studies showed that the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected respectively to the contralateral lateral, medial, caudal and rostral SC in rodents. While this topological pattern is preserved in the intraorbital optic nerve, it was shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly in the superior but not inferior retina and optic nerve. The results of this study demonstrated the sensitivity of submillimeter-resolution MEMRI for in vivo, 3D mapping of the precise retinotopic projections in SC upon reduced anterograde axonal transport of Mn(2+) ions from localized regions of the anterior visual pathways to the subcortical midbrain nuclei. Future MEMRI studies are envisioned that measure the topographic changes in brain development, diseases, plasticity and regeneration therapies in a global and longitudinal setting.

Neonatal monocular enucleation (ME) is often employed to study the developmental mechanisms underlying visual perception and the cross-modal changes in the central nervous system caused by early loss of the visual input. However, underlying biochemical or metabolic mechanisms that accompany the morphological, physiological and behavioral changes after ME are not fully understood. Male Sprague-Dawley rats (N=14) were prepared and divided into 2 groups. The enucleated group (N=8) underwent right ME (right eye removal) at postnatal day 10, while the normal group (N=6) was intact and served as a control. Three weeks after ME, single voxel proton magnetic resonance spectroscopy ((1)H MRS) was performed over the visual cortex of each hemisphere in all animals with a point-resolved spectroscopy (PRESS) sequence at 7 T. The taurine (Tau) and N-acetylaspartate (NAA) levels were found to be significantly lower in the left visual cortex (contralateral to enucleated eye) for enucleated animals. Such metabolic changes measured in vivo likely reflected the cortical degeneration associated with the reduction of neurons, axon terminals and overall neuronal activity. This study also demonstrated that (1)H MRS approach has the potential to characterize neonatal ME and other developmental neuroplasticity models noninvasively for the biochemical and metabolic processes involved.

Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N-acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects.

UNLABELLED: To speed up the process of central nervous system (CNS) recovery after injury, the need for real-time measurement of axon regeneration in vivo is essential to assess the extent of injury, as well as the optimal timing and delivery of therapeutics and rehabilitation. It was necessary to develop a chronic animal model with an in vivo measurement technique to provide a real-time monitoring and feedback system. Using the framework of the 4 P's of CNS regeneration (Preserve, Permit, Promote and Plasticity) as a guide, combined with noninvasive manganese-enhanced magnetic resonance imaging (MEMRI), we show a successful chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. We also show that a chronic optic tract (OT) lesion is able to heal, and axons are able to regenerate, when treated with a self-assembling nanofiber peptide scaffold (SAPNS). FROM THE CLINICAL EDITOR: The authors of this study demonstrate the development of a chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. In addition, they determined that chronic optic tract lesions are able to heal with axonal regeneration when treated with a self-assembling nanofiber peptide scaffold (SAPNS).