In vivo manganese-enhanced MRI and diffusion tensor imaging of developing and impaired visual brains

This study explored the feasibility of high-resolution Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) for in vivo assessments of the development and reorganization of retinal and visual callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Using MEMRI, intravitreal Mn 2+ injection into one eye resulted in maximal T1-weighted hyperintensity in neonatal contralateral superior colliculus (SC) 8 hours after administration, whereas in adult contralateral SC signal increase continued at 1 day post-injection. Notably, mild but significant Mn 2+ enhancement was observed in the ipsilateral SC in normal neonatal rats, and in adult rats after neonatal monocular enucleation (ME) but not in normal adult rats. Upon intracortical Mn 2+ injection to the visual cortex, neonatal binocularly-enucleated (BE) rats showed an enhancement of a larger projection area, via the splenium of corpus callosum to the V1/V2 transition zone of the contralateral hemisphere in comparison to normal rats. For DTI, the retinal pathways projected from the enucleated eyes possessed lower fractional anisotropy (FA) 6 weeks after BE and ME. Interestingly, in the optic nerve projected from the remaining eye in ME rats a significantly higher FA was observed compared to normal rats. The results of this study are potentially important for understanding the axonal transport, microstructural reorganization and functional activities in the living visual brain during early postnatal development and plasticity in a global and longitudinal setting. © 2011 IEEE.published_or_final_versionThe 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2011), Boston, MA., 30 August-3 September 2011. In IEEE Engineering in Medicine and Biology Society Conference Proceedings, 2011, p. 7005-700

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration

Manganese-enhanced magnetic resonance imaging (MEMRI) rose to prominence in the 1990s as a sensitive approach to high contrast imaging. Following the discovery of manganese conductance through calcium-permeable channels, MEMRI applications expanded to include functional imaging in the central nervous system (CNS) and other body systems. MEMRI has since been employed in the investigation of physiology in many animal models and in humans. Here, we review historical perspectives that follow the evolution of applied MRI research into MEMRI with particular focus on its potential toxicity. Furthermore, we discuss the more current in vivo investigative uses of MEMRI in CNS investigations and the brief but decorated clinical usage of chelated manganese compound mangafodipir in humans

Assessing Functional Deficits at Optic Neuritis Onset in EAE Mice Using Manganese-Enhanced MRI (MEMRI) and Diffusion fMRI

Optic neuritis: ON) is frequently a first sign of multiple sclerosis: MS), which is an inflammatory demyelinative disease of the central nerve system: CNS), including brain, optic nerve, and spinal cord. Investigating ON provides an approach to improve MS diagnosis and treatment monitoring. Experimental autoimmune encephalomyelitis: EAE) is a widely used animal model of MS and exhibits pathologies similar to the human disease. Magnetic resonance imaging: MRI) is a non-invasive tool to detect disease progress and as a standard diagnose procedure for MS in the clinic. In biological samples, the hydrogen nuclei are used to produce the MR signal due to its abundance in water and fat. As a result of tissue microstructural differences, 1H nuclei exhibit tissue-specific and pathology-specific relaxation and diffusion properties, which are reflected in the resulting MR image contrast. Therefore, the pathologies of MS, such as inflammation, demyelination, and axonal injury can be detected using different MR-related tools, including T1- and T2-weighted imaging, diffusion-weighted imaging, and diffusion tensor imaging, and so on. Importantly, direct non-invasive assessment of functional deficits could be important for understanding pathology mechanisms or provide a useful bio-index to validate treatment strategies. In this dissertation, manganese-enhanced MRI: MEMRI) and diffusion fMRI were introduced to explore the functional deficits, including axonal transport disruption and axon-activity dysfunction, at optic neuritis onset in EAE mice

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration

Manganese-enhanced magnetic resonance imaging (MEMRI) rose to prominence in the 1990s as a sensitive approach to high contrast imaging. Following the discovery of manganese conductance through calcium-permeable channels, MEMRI applications expanded to include functional imaging in the central nervous system (CNS) and other body systems. MEMRI has since been employed in the investigation of physiology in many animal models and in humans. Here, we review historical perspectives that follow the evolution of applied MRI research into MEMRI with particular focus on its potential toxicity. Furthermore, we discuss the more current in vivo investigative uses of MEMRI in CNS investigations and the brief but decorated clinical usage of chelated manganese compound mangafodipir in humans

Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T₂water ¹H relaxation or ¹H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan <it>in vivo </it>brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.</p> <p>Results</p> <p>Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T₂-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T₂water ¹H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T₂. Importantly, morphological, but not T₂relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.</p> <p>Conclusions</p> <p>A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T₂relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration <it>in vivo</it>.</p