Govind Nair

Structural and functional MRI reveals multiple retinal layers.

MRI is a noninvasive diagnostic modality that reveals anatomy, physiology, and function in vivo without depth limitation or optical interference. MRI application to the retina, however, remains challenging. We improved spatial resolution to resolve layer-specific structure and functional responses in the retina and confirmed the laminar resolution in an established animal model of retinal degeneration. Structural MRI of normal rat retinas revealed three bands corresponding histologically to (i) the combined ganglion cell layer/inner nuclear layer plus the embedded retinal vessels, (ii) the avascular outer nuclear (photoreceptor) layer and its photoreceptor segments, and (iii) the choroidal vascular layer. Imaging with an intravascular contrast agent (gadolinium-diethylene-tri-amine-pentaacetic acid) enhanced the retinal and choroidal vascular layers bounding the retina, but not the avascular outer nuclear layer and the vitreous. Similarly, blood-oxygen-level-dependent (BOLD) functional MRI revealed layer-specific responses to hyperoxia and hypercapnia. Importantly, layer-specific BOLD responses in the two vascular layers were divergent, suggesting the two vasculatures are differentially regulated. To corroborate sensitivity and specificity, we applied layer-specific MRI to document photoreceptor degeneration in Royal College of Surgeons rats. Consistent with histology, layer-specific MRI detected degeneration of the outer nuclear layer. Surprisingly, MRI revealed increased thickness in the choroidal vascular layer and diminished BOLD responses to hyperoxia and hypercapnia in the Royal College of Surgeons rat retinas, suggesting perturbation of vascular reactivity secondary to photoreceptor loss. We conclude that MRI is a powerful investigative tool capable of resolving lamina-specific structures and functional responses in the retina as well as probing lamina-specific changes in retinal diseases.

The neural consequences of repeated cocaine exposure revealed by functional MRI in awake rats

The use of functional magnetic resonance imaging (fMRI) in animal models of cocaine addiction is an invaluable tool for investigating the neuroadaptations that lead to this psychiatric disorder. We used blood-oxygen-level-dependent (BOLD) MRI in awake rats to identify the neuronal circuits affected by repeated cocaine administration. Rats were given an injection of cocaine (15 mg/kg, i.p.) or its vehicle for 7 days, abstained from injections for 1 week, and challenged with an intracerebroventricular cocaine injection during functional imaging. Acute cocaine produced robust positive BOLD responses across well-known monoamine-enriched brain regions, such as the prefrontal cortex, nucleus accumbens, dorsal striatum, sensory cortex, hippocampus, thalamus, and midbrain areas. However, repeated cocaine administration resulted in lower BOLD responses in the prefrontal cortex, agranular insular cortex, nucleus accumbens, ventral pallidum, and dorsomedial thalamus, among other brain regions. Reductions in BOLD intensity were not associated with variations in cerebrovascular reactivity between drug naïve rats and those repeatedly exposed to cocaine. Therefore, the lower metabolic activation in response to cocaine could reflect a reduced neuronal and/or synaptic activity upon repeated administration.

Utility of axial and radial diffusivity from diffusion tensor MRI as markers of neurodegeneration in amyotrophic lateral sclerosis.

OBJECTIVE To investigate changes in the diffusion tensor imaging measures, axial diffusivity and radial diffusivity, in addition to the more commonly used fractional anisotropy and mean diffusivity, in patients with amyotrophic lateral sclerosis (ALS) using the voxel-based statistical analysis tool, tract based spatial statistics. METHODS We studied 12 patients with ALS and 19 normal controls using diffusion tensor imaging; tract based spatial statistics was applied to study changes in fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity values in brain white matter tracts. ALS patients were evaluated using clinical examination, administration of the revised ALS functional rating scale and measurement of the forced vital capacity. RESULTS In ALS patients, we found significant increases in axial diffusivity, radial diffusivity, and mean diffusivity and significant decreases in fractional anisotropy. Increases in axial diffusivity and radial diffusivity were more widespread and more prominent in the corticospinal tract than the decreases in fractional anisotropy. The decreases in fractional anisotropy were evident only in the corona radiata and genu of the corpus callosum. CONCLUSION In ALS, axial diffusivity and radial diffusivity may be useful diffusion tensor imaging-derived indices to consider in addition to fractional anisotropy and mean diffusivity to aid in demonstrating neurodegenerative changes.

Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis

Objective: To determine the frequency and nature of leptomeningeal contrast enhancement in multiple sclerosis (MS) via in vivo 3-tesla postcontrast T2-weighted, fluid-attenuated inversion recovery (FLAIR) MRI and 7-tesla postmortem MRI–pathology correlation. Methods: Brain MRI, using the postcontrast T2-weighted, FLAIR technique, was prospectively collected in 299 MS cases and 37 age-matched neurologically healthy controls. Expert raters evaluated focal gadolinium enhancement in the leptomeningeal compartment. Two progressive MS cases came to autopsy after in vivo MRI characterization. Pathologic and immunohistochemical examination assessed the association of enhancement with leptomeningeal inflammation and adjacent cortical demyelination. Results: Focal contrast enhancement was detected in the leptomeningeal compartment in 74 of 299 MS cases (25%) vs 1 of 37 neurologically healthy controls (2.7%; p = 0.001). Enhancement was nearly twice as frequent (p = 0.009) in progressive MS (39/118 cases, 33%) as in relapsing-remitting MS (35/181, 19%). Enhancing foci generally remained stable throughout the evaluation period (up to 5.5 years). Pathology showed perivascular lymphocytic and mononuclear infiltration in the enhancing areas in association with flanking subpial cortical demyelination. Conclusion: Leptomeningeal contrast enhancement occurs frequently in MS and is a noninvasive, in vivo marker of inflammation and associated subpial demyelination. It might therefore enable testing of new treatments aimed at eliminating this inflammation and potentially arresting progressive MS.

Layer-specific anatomical, physiological and functional MRI of the retina

Most retinal imaging has been performed using optical techniques. This paper reviews alternative retinal imaging methods based on MRI performed with spatial resolution sufficient to resolve multiple well‐defined retinal layers. The development of these MRI technologies to study retinal anatomy, physiology (blood flow, blood volume, and oxygenation) and function, and their applications to the study of normal retinas, retinal degeneration and diabetic retinopathy in animal models are discussed. Although the spatiotemporal resolution of MRI is poorer than that of optical imaging techniques, it is unhampered by media opacity and can thus image all retinal and pararetinal structures, and has the potential to provide multiple unique clinically relevant data in a single setting and could thus complement existing retinal imaging techniques. In turn, the highly structured retina with well‐defined layers is an excellent model for advancing emerging high‐resolution anatomical, physiological and functional MRI technologies. Copyright

Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS

Objective: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls. Methods: A cross-sectional study of 1H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined. Results: NAA/Cr and NAA/Myo ratios are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls. Conclusions: Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic signs of disease. These changes reflect a reduction in NAA/Cr and NAA/Myo. Neurometabolic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggests that neurometabolic changes occur early in the course of the disease process.

Echo-planar BOLD-fMRI of mice on a narrow-bore 9.4 T magnet

The feasibility of BOLD fMRI in association with electrical somatosensory stimulation on spontaneously breathing, isoflurane‐anesthetized mice was investigated using spin‐echo, echo‐planar imaging (EPI) on a vertical narrow‐bore 9.4 T magnet. Three experiments were performed to derive an optimal fMRI protocol. In Experiment 1 (n = 9), spin‐echo BOLD responses to 10% CO2 challenge under graded isoflurane (0.25–1.25%) ranged from 10 ± 2% to 3.5 ± 0.9%; the optimal BOLD contrast‐to‐noise ratio peaked at 0.75% isoflurane. In Experiment 2 (n = 6), hindpaw somatosensory stimulations using 1–7 mA under 0.75% isoflurane revealed the optimal BOLD response was at 6 mA. In Experiment 3 (n = 5), BOLD responses to 4 and 6 mA stimulation under 0.75% and 1% isoflurane were evaluated in detail, confirming the optimal conditions in Experiment 2. These results demonstrated that BOLD fMRI using single‐shot, spin‐echo EPI in a mouse somatosensory stimulation model could be routinely performed on high‐field, vertical, narrow‐bore magnets. This protocol might prove useful for fMRI studies of transgenic mice. Magn Reson Med 52:430–434, 2004.

Magnetic resonance imaging of tissue and vascular layers in the cat retina.

To report the visual resolution of multiple cell and vascular “layers” in the cat retina using MRI.

Automatic Magnetic Resonance Spinal Cord Segmentation with Topology Constraints for Variable Fields of View

Spinal cord segmentation is an important step in the analysis of neurological diseases such as multiple sclerosis. Several studies have shown correlations between disease progression and metrics relating to spinal cord atrophy and shape changes. Current practices primarily involve segmenting the spinal cord manually or semi-automatically, which can be inconsistent and time-consuming for large datasets. An automatic method that segments the spinal cord and cerebrospinal fluid from magnetic resonance images is presented. The method uses a deformable atlas and topology constraints to produce results that are robust to noise and artifacts. The method is designed to be easily extended to new data with different modalities, resolutions, and fields of view. Validation was performed on two distinct datasets. The first consists of magnetization transfer-prepared T2*-weighted gradient-echo MRI centered only on the cervical vertebrae (C1-C5). The second consists of T1-weighted MRI that covers both the cervical and portions of the thoracic vertebrae (C1-T4). Results were found to be highly accurate in comparison to manual segmentations. A pilot study was carried out to demonstrate the potential utility of this new method for research and clinical studies of multiple sclerosis.

Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI

Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.