Nicholas A. Bock

Multiple-mouse MRI.

Several theoretical parallel‐imaging approaches are evaluated that seek to improve the efficiency of an MRI experiment involving multiple small samples, such as mice. The best method for our mouse phenotyping application is chosen in terms of efficiency and ease of implementation, and the approach is demonstrated at 1.5 T on a clinical scanner with an array of four shielded birdcage coils with four parallel receivers. Electronic interactions between the receiver channels in the system are quantified and a novel sensitivity‐encoding (SENSE)‐like postprocessing method is described to remove the resulting image ghosts. In parallel imaging with a four‐coil array, the time required for three‐dimensional (3D) high‐resolution imaging of four mice is reduced to one‐fourth the time that it would take to image the mice sequentially. Magn Reson Med 49:158–167, 2003.

Manganese-Enhanced MRI: An Exceptional Tool in Translational Neuroimaging

The metal manganese is a potent magnetic resonance imaging (MRI) contrast agent that is essential in cell biology. Manganese-enhanced magnetic resonance imaging (MEMRI) is providing unique information in an ever-growing number of applications aimed at understanding the anatomy, the integration, and the function of neural circuits both in normal brain physiology as well as in translational models of brain disease. A major drawback to the use of manganese as a contrast agent, however, is its cellular toxicity. Therefore, paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest using as low a dose as possible while preserving detectability by MRI. In the present work, the different approaches to MEMRI in translational neuroimaging are reviewed and challenges for future identified from a practical standpoint.

High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model

High-grade gliomas are devastating brain tumors associated with a mean survival of <50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss.

Visualizing the entire cortical myelination pattern in marmosets with magnetic resonance imaging

Myeloarchitecture, the pattern of myelin density across the cerebral cortex, has long been visualized in histological sections to identify distinct anatomical areas of the cortex. In humans, two-dimensional (2D) magnetic resonance imaging (MRI) has been used to visualize myeloarchitecture in select areas of the cortex, such as the stripe of Gennari in the primary visual cortex and Heschls gyrus in the primary auditory cortex. Here, we investigated the use of MRI contrast based on longitudinal relaxation time (T(1)) to visualize myeloarchitecture in vivo over the entire cortex of the common marmoset (Callithrix jacchus), a small non-human primate that is becoming increasingly important in neuroscience and neurobiology research. Using quantitative T(1) mapping, we found that T(1) at 7T in a cortical region with a high myelin content was 15% shorter than T(1) in a region with a low myelin content. To maximize this T(1) contrast for imaging cortical myelination patterns, we optimized a magnetization-prepared rapidly acquired gradient echo (MP-RAGE) sequence. In whole-brain, 3D T(1)-weighted images made in vivo with the sequence, we identified six major cortical areas with high myelination and confirmed the results with histological sections stained for myelin. We also identified several subtle features of myeloarchitecture, showing the sensitivity of our technique. The ability to image myeloarchitecture over the entire cortex may prove useful in studies of longitudinal changes of the topography of the cortex associated with development and neuronal plasticity, as well as for guiding and confirming the location of functional measurements.

Multiple mouse biological loading and monitoring system for MRI

The use of mice to study models of human disease has resulted in a surge of interest in developing mouse MRI. The ability to take 3D, high‐resolution images of live mice allows significant insight into anatomy and function. However, with imaging times on the order of hours, high throughput of specimens has been problematic. To facilitate high throughput, concurrent imaging of multiple mice has been developed; however, this poses further complexities regarding the ease and rapidity of loading several animals. In this study, custom‐built equipment was developed to streamline the preparation process and to safely maintain seven mice during a multiple‐mouse imaging session. Total preparation time for seven mice was ∼24 min. ECG and temperature were monitored throughout the scan and maintained by regulating anesthetic and heating. Proof of principle was demonstrated in a 3‐h imaging session of seven mice. Magn Reson Med 52:709–715, 2004.

In vivo multiple-mouse MRI at 7 Tesla

We developed a live high‐field multiple‐mouse magnetic resonance imaging method to increase the throughput of imaging studies involving large numbers of mice. Phantom experiments were performed in 7 shielded radiofrequency (RF) coils for concurrent imaging on a 7 Tesla MRI scanner outfitted with multiple transmit and receive channels to confirm uniform signal‐to‐noise ratio and minimal ghost artifacts across images from the different RF coils. Grid phantoms were used to measure image distortion in different positions in the coils. The brains of 7 live mice were imaged in 3D in the RF coil array, and a second array of 16 RF coils was used to 3D image the whole bodies of 16 fixed, contrast agent‐perfused mice. The images of the 7 live mouse brains at 156 μm isotropic resolution and the 16 whole fixed mice at 100 μm isotropic resolution were of high quality and free of artifacts. We have thus shown that multiple‐mouse MRI increases throughput for live and fixed mouse experiments by a factor equaling the number of RF coils in the scanner. Magn Reson Med, 2005.

A combined histological and MRI brain atlas of the common marmoset monkey, Callithrix jacchus.

The common marmoset, Callithrix jacchus, is of growing importance for research in neuroscience and related fields. In the present work, we describe a combined histological and magnetic resonance imaging (MRI) atlas constructed from the brains of two adult female marmosets. Histological sections were processed from Nissl staining and digitized to produce an atlas in a large format that facilitates visualization of structures with significant detail. Naming of identifiable brain structures was performed utilizing current terminology. The histological sections and a simplified schematic atlas are available online at http://udn.nichd.nih.gov/brainatlas_home.html.

In Vivo Magnetic Resonance Imaging and Semiautomated Image Analysis Extend the Brain Phenotype for cdf/cdf Mice

Magnetic resonance imaging and computer image analysis in human clinical studies effectively identify abnormal neuroanatomy in disease populations. As more mouse models of neurological disorders are discovered, such an approach may prove useful for translational studies. Here, we demonstrate the effectiveness of a similar strategy for mouse neuroscience studies by phenotyping mice with the cerebellar deficient folia (cdf) mutation. Using in vivo multiple-mouse magnetic resonance imaging for increased throughput, we imaged groups of cdf mutant, heterozygous, and wild-type mice and made an atlas-based segmentation of the structures in 15 individual brains. We then performed computer automated volume measurements on the structures. We found a reduced cerebellar volume in the cdf mutants, which was expected, but we also found a new phenotype in the inferior colliculus and the olfactory bulbs. Subsequent local histology revealed additional cytoarchitectural abnormalities in the olfactory bulbs. This demonstrates the utility of anatomical magnetic resonance imaging and semiautomated image analysis for detecting abnormal neuroarchitecture in mutant mice.

Retrospective gating for mouse cardiac MRI.

Cardiac MR imaging in small animals presents some difficulties due to shorter cardiac cycles and smaller dimensions than in human beings, but prospectively gated techniques have been successfully applied. As with human imaging, there may be certain applications in animal imaging for which retrospective gating is preferable to prospective gating. For example, cardiac imaging in multiple mice simultaneously is one such application. In this work we investigate the use of retrospective gating for cardiac imaging in a mouse. Using a three‐dimensional imaging protocol, we show that image quality with retrospective gating is comparable to prospectively gated imaging. We conclude that retrospective gating is applicable for small animal cardiac MRI and show how it can be applied to the problem of cardiac MRI in multiple mice. Magn Reson Med, 2006.

Functional Mapping of Face-Selective Regions in the Extrastriate Visual Cortex of the Marmoset

The cerebral cortex of humans and macaques has specialized regions for processing faces and other visual stimulus categories. It is unknown whether a similar functional organization exists in New World monkeys, such as the common marmoset (Callithrix jacchus), a species of growing interest as a primate model in neuroscience. To address this question, we measured selective neural responses in the brain of four awake marmosets trained to fix their gaze upon images of faces, bodies, objects, and control patterns. In two of the subjects, we measured high gamma-range field potentials from electrocorticography arrays implanted over a large portion of the occipital and inferotemporal cortex. In the other two subjects, we measured BOLD fMRI responses across the entire brain. Both techniques revealed robust, regionally specific patterns of category-selective neural responses. We report that at least six face-selective patches mark the occipitotemporal pathway of the marmoset, with the most anterior patches showing the strongest preference for faces over other stimuli. The similar appearance of these patches to previous findings in macaques and humans, including their apparent arrangement in two parallel pathways, suggests that core elements of the face processing network were present in the common anthropoid primate ancestor living ∼35 million years ago. The findings also identify the marmoset as a viable animal model system for studying specialized neural mechanisms related to high-level social visual perception in humans.