Manganese-enhanced MRI of hypoxic-ischemic brain injuries using Mn-DPDP

Theme: Engineering the Future of BiomedicineIn this study, Mn-dipyridoxaldiphosphate (MnDPDP), a clinically approved manganese contrast agent for hepatic and pancreatic imaging, was demonstrated for the first time for manganese-enhanced MRI (MEMRI) in brains of normal young rats (n=4) and rats with hypoxic-ischemic (H-I) insult at postnatal day 7 (n=8). After a single intraperitoneal injection of low dosage with 0.1μmol/g in postnatal 14 days, 2D T1-weighted image (T1WIs), T1 maps, T2-weighted images (T2WIs) and T2 maps were acquired at 7 Tesla 1 day before, 1 day and 7 days after MnDPDP injection. The image contrast changes induced by MnDPDP appeared as the hyperintensity in T1WIs and the hypointensity in T2WIs. T1and T2 values decreased in the regions of Mn enhancement. Such enhancement presented as a delayed pattern that was more pronounced in 7 day after MnDPDP injection, suggesting the sustained Mn accumulation due to MnDPDP. Moreover, the MnDPDP enhancement in H-I brains was more pronounced in the lesion sites and was easily detectable in T1WI, T1 map, T2WI and T2 map. The results demonstrated here support the possibility of using MnDPDP as a 'slow release' Mn2+ for clinical diagnosis of various neuropathologies. ©2009 IEEE.published_or_final_versionThe 31st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2009), Minneapolis, MN., 3-6 September 2009. In Proceedings of the 31st EMBC, 2009, p. 4775-477

Tract-based spatial statistics (TBSS): application to detecting white matter tract variation in mild hypoxic-ischemic neonates

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.published_or_final_versio

In vivo manganese-enhanced MRI for visuotopic brain mapping

This study explored the feasibility of localized manganese-enhanced MRI (MEMRI) via 3 different routes of Mn(2+) administrations for visuotopic brain mapping of retinal, callosal, cortico-subcortical, transsynaptic and horizontal connections in normal adult rats. Upon fractionated intravitreal Mn(2+) injection, Mn enhancements were observed in the contralateral superior colliculus (SC) and lateral geniculate nucleus (LGN) by 45-60% at 1-3 days after initial Mn(2+) injection and in the contralateral primary visual cortex (V1) by about 10% at 2-3 days after initial Mn(2+) injection. Direct, single-dose Mn(2+) injection to the LGN resulted in Mn enhancement by 13-21% in V1 and 8-11% in SC of the ipsilateral hemisphere at 8 to 24 hours after Mn(2+) administration. Intracortical, single-dose Mn(2+) injection to the visual cortex resulted in Mn enhancement by 53-65% in ipsilateral LGN, 15-26% in ipsilateral SC, 32-34% in the splenium of corpus callosum and 17-25% in contralateral V1/V2 transition zone at 8 to 24 hours after Mn(2+) administration. Notably, some patchy patterns were apparent near the V1/V2 border of the contralateral hemisphere. Laminar-specific horizontal cortical connections were also observed in the ipsilateral hemisphere. The current results demonstrated the sensitivity of MEMRI for assessing the neuroarchitecture of the visual brains in vivo without depth-limitation, and may possess great potentials for studying the basic neural components and connections in the visual system longitudinally during development, plasticity, pharmacological interventions and genetic modifications.published_or_final_versio

Functional MRI of postnatal visual development in normal rat superior colliculi

Theme: Engineering the Future of BiomedicineThis study employed blood oxygenation level-dependent functional MRI (BOLD-fMRI) to evaluate the visual responses in the superior colliculus of the developing rat brain from the time of eyelid opening to adulthood. Upon flash illumination to the contralateral eye, the regional BOLD response underwent a systematic increase in amplitude with age especially after the third postnatal week. However, no significant difference in BOLD signal increase was found between postnatal days 14 and 21. Our results constitute the first fMRI report in demonstrating the critical period of visual functions in the rat brain during maturation. This can be potentially useful in establishing the links between changes in relation to visual sensory development. ©2009 IEEE.published_or_final_versionThe 31st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2009), Minneapolis, MN., 3-6 September 2009. In Proceedings of the 31st EMBC, 2009, p. 4436-443

Early detection of neurodegeneration in brain ischemia by manganese-enhanced MRI

This study aims to employ in vivo manganese-enhanced MRI (MEMRI) to detect neurodegenerative changes in two models of brain ischemia, photothrombotic cortical injury (PCI) and transient middle cerebral artery occlusion (MCAO) in rodents. After systemic Mn 2+ injection to both ischemic models, a close pattern of Tl-weighted hyperintensity was observed throughout different brain regions in comparison to the distribution of GFAP, MnSOD and GS immunoreactivities, whereby conventional MRI could hardly detect such. In addition, the infarct volumes in the posterior parts of the brain had significantly reduced after Mn 2+ injection to the MCAO model. It is suggested that exogenous Mn 2+ injection may provide enhanced MEMRI detection of oxidative stress and gliosis early after brain ischemia. Manganese may also mediate infarctions at remote brain regions in transient focal cerebral ischemia before delayed secondary damage takes place. © 2008 IEEE.published_or_final_versionThe 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBS) 2008, Vancouver, BC., 20-25 August 2008. in Proceedings of the 30th EMBS, 2008, p. 3884-388

Magnetic resonance imaging of migrating neuronal precursors in normal and hypoxic-ischemic neonatal rat brains by intraventricular MPIO labeling

Proceedings of the IEEE Engineering in Medicine and Biology Society Conference, 2008, p. 363-366In this study, 10-day-old normal rats (n=6) and hypoxic-ischemic (H-I) neonatal rats (n=6) were injected with the micronsized iron oxide particles (MPIOs) into the anterior lateral ventricle. 2D and 3D high-spatial resolution MRI were performed with a 7T animal scanner 1 day before the MPIOs injection and hour 3, day 3, day 7 and day 14 after the MPIOs injection. Intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU) were used to label newly produced cells, and were given thrice daily for 2 days before sacrifice. Immunohistochemistry and Prussian blue staining indicated that iron particles were inside the nestin+ and BrdU+ neural progenitor cells (NPCs), glial-fibrillary-acidic-protein-positive (GFAP+) astrocytes-like progenitor cells, and neuronal-nuclei-positive (NeuN+) mature neurons. Here we demonstrate that, in normal neonatal rat brain, the migrating pathway of the endogenous NPCs with MPIO is mainly along the rostral migratory stream to the olfactory bulb. In H-I neonatal rat brain, the migration of endogenous NPCs with MPIO is mainly towards the ischemic regions. Therefore, in vivo magnetic cell labeling of endogenous NPCs with MPIO and subsequently non-invasive, serial MRI monitoring should open up a new approach to probe into the mechanism of cell migration in the developmental brain under physiological and pathologic conditions. © 2008 IEEE.published_or_final_versio

Longitudinal Assessments of Normal and Perilesional Tissues in Focal Brain Ischemia and Partial Optic Nerve Injury with Manganese-enhanced MRI

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Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells

Prenatal Irradiation-Induced Hippocampal Abnormalities in Rats Evaluated Using Manganese-Enhanced MRI

The aim of this study was to characterize hippocampal abnormalities in rats after prenatal x-ray irradiation using manganese-enhanced MRI (MEMRI). All radiation-exposed rat brains showed a reduced volume with prominent dilatation of lateral ventricles. Moreover, MEMRI-enhanced areas within the hippocampus were reduced in volumes by approximately 25% of controls, although the entire volume of hippocampus was decreased by approximately 50% of controls. MEMRI signals were enhanced strongly in the hilus and granular layer of the dentate gyrus (DG) and the pyramidal layer and infrapyramidal region of the CA3 region, and moderately along the CA1/2 pyramidal cell layer in the control rats. In radiation-exposed rats, MEMRI signals in the CA1/2 regions disappeared due to disrupting their laminar organization, although strong MEMRI signals were sustained in the DG and CA3 regions. Histopathological examinations in radiation-exposed rats revealed disorganizations of the DG granule cell layer and the CA3 pyramidal cell layer with reducing the cell density. The CA1/2 pyramidal cell layer was disrupted by invading ectopic cell mass. Neural cell adhesion molecule (NCAM)-positive fiber bundles were sustained in radiation-exposed rats, although they distributed aberrantly in the suprapyramidal CA3 region with a slight reduction of NCAM staining. Furthermore, glial components consisted largely by astrocytes and minor by microglia were densely distributed in the DG rather than in other hippocampal regions, and their density radiation-exposed rats. In conclusion, MEMRI signal enhancements could delineate different neuronal and/or glial components among hippocampal regions. We characterized microstructures of the deformed hippocampus as well as its macrostructures in a prenatally radiation-exposed rat model using in vivo MEMRI. The present findings provide advantageous information for detecting nondestructively hippocampal deformations in neurodevelopmental disorders