Functional mapping of the auditory tract in rodent tinnitus model using manganese-enhanced magnetic resonance imaging.

Animal models of salicylate-induced tinnitus have demonstrated that salicylate modulates neuronal activity in several brain structures leading to neuronal hyperactivity in auditory and non-auditory brain areas. In addition, these animal tinnitus models indicate that tinnitus can be a perceptual consequence of altered spontaneous neural activity along the auditory pathway. Peripheral and/or central effects of salicylate can account for neuronal activity changes in salicylate-induced tinnitus. Because of this ambiguity, an in vivo imaging study would be able to address the peripheral and/or central involvement of salicylate-induced tinnitus. Therefore, in the present study, we developed a novel manganese-enhanced magnetic resonance imaging (MEMRI) method to map the in vivo functional auditory tract in a salicylate-induced tinnitus animal model by administrating manganese through the round window. We found that acute salicylate-induced tinnitus resulted in higher manganese uptake in the cochlea and in the central auditory structures. Furthermore, serial MRI scans demonstrated that the manganese signal increased in an anterograde fashion from the cochlea to the cochlear nucleus. Therefore, our in vivo MEMRI data suggest that acute salicylate-induced tinnitus is associated with higher spontaneous neural activity both in peripheral and central auditory pathways.

Surface coated Eu(OH)3 nanorods: a facile synthesis, characterization, MR relaxivities and in vitro cytotoxicity.

The water-soluble and biocompatible D-glucuronic acid coated Eu(OH)3 nanorods (average thickness x average length = 9.0 x 118.3 nm) have been prepared in one-pot synthesis. The D-glucuronic acid coated Eu(OH)3 nanorods showed a strong fluorescence at approximately 600 nm with a narrow emission band width. A cytotoxicity test by using DU145 cells showed that D-glucuronic acid coated Eu(OH)3 nanorods are not toxic up to 100 microM, making them a promising candidate for biomedical applications such as fluorescent imaging. The minimum Eu concentration needed for a conventional confocal imaging was estimated to be approximately 0.1 mM. Therefore, D-glucuronic acid coated Eu(OH)3 nanorods can be applied to fluorescent imaging. However, a very tiny magnetization of approximately 1.2 emu/g at room temperature and at an applied field of 5 tesla was observed. As a result, very small r1 and r2 water proton relaxivities were estimated, implying that surface coated Eu(OH)3 nanorods are not sufficient for MRI contrast agents.

Functional activity mapping of rat auditory pathway after intratympanic manganese administration.

In the present study, we report a new method of manganese enhanced magnetic resonance imaging (MEMRI) using intratympanic (IT) manganese administration. We explore Mn²âº uptake from the middle ear cavity into the cochlea through mechanically gated ion channels of the hair cell and also functional auditory tract tracing without the use of excessive auditory stimuli for a long time period outside the scanner. After manganese administration in animals with normal hearing and unilateral deafness, T1-weighted MR images were obtained for up to 48 h with a 3.0 T MR imager. In normal rats, the mean signal-to-noise ratio (SNR) at each region of interest on the auditory pathway was significantly higher in the IT injection group than in the intraperitoneal (IP) injection group (P<0.05). Furthermore, the cochlea showed Mn²âº signal enhancement only in the IT injection group. In unilateral deafness rats, the IT injection of Mn²âº into the deaf-side middle ear cavity demonstrated signal enhancement in the cochlea but not in other auditory structures without axonal transport of Mn²âº along the auditory pathway. On the other hand, the IT injection of Mn²âº into the normal-side middle ear cavity demonstrated that the mean SNRs at the cochlea, cochlear nucleus, superior olivary complex, lateral lemniscus and inferior colliculus were significantly higher in the ipsilateral auditory pathway than in the contralateral pathway (P<0.05). For the IP injection group, the mean SNRs at each auditory structure, except the cochlea, increased bilaterally. In conclusion, the present work demonstrated the potential advantages of a new IT MEMRI over conventional systemic injection strategies in that (i) the functional auditory tract tracing initiated by the hair cell function is possible and (ii) the axonal transport of Mn²âº ions by trans-synaptic activity is possible without auditory stimulation for a long time period outside MR scanner.

Gold-coated iron oxide nanoparticles as a T2 contrast agent in magnetic resonance imaging.

Gold-coated iron oxide (Fe3O4) nanoparticles were synthesized for use as a T2 contrast agent in magnetic resonance imaging (MRI). The coated nanoparticles were spherical in shape with an average diameter of 20 nm. The gold shell was about 2 nm thick. The bonding status of the gold on the nanoparticle surfaces was checked using a Fourier transform infrared spectrometer (FTIR). The FTIR spectra confirmed the attachment of homocysteine, in the form of thiolates, to the Au shell of the Au-Fe3O4 nanoparticles. The relaxivity ratio, R2/R1, for the coated nanoparticles was 3-fold higher than that of a commercial contrast agent, Resovist, which showed the potential for their use as a T2 contrast agent with high efficacy. In animal experiments, the presence of the nanoparticles in rat liver resulted in a 71% decrease in signal intensity in T2-weighted MR images, indicating that our gold-coated iron oxide nanoparticles are suitable for use as a T2 contrast agent in MRI.

Altered executive function in the lead-exposed brain: A functional magnetic resonance imaging study.

INTRODUCTION: It is well known that lead exposure induces neurotoxic effects, which can result in dysfunction in a variety of cognitive capacities including executive function. However, few studies have used fMRI to examine the direct neural correlates of executive function in participants with past lead exposure. Therefore, this study aimed to investigate possible alterations in the neural correlates of executive function in the previously lead-exposed brain. METHODS: Forty-three lead-exposed and 41 healthy participants were enrolled. During the fMRI scans, participants performed two modified versions of the Wisconsin Card Sorting Task (WCST) differing in cognitive demand, and a task that established a high-level baseline condition (HLB). RESULTS: The neural activation of left dorsolateral prefrontal cortex was greater in healthy controls than in participants with lead exposure when contrasting the difficult version of the WCST with the HLB. Moreover, cortical activation was found to be inversely associated with blood lead concentration after controlling for covariates. DISCUSSION: These data suggest that lead exposure can induce functional abnormalities in distributed cortical networks related to executive function, and that lead-induced neurotoxicity may be persistent rather than transient.

Lead-induced impairments in the neural processes related to working memory function.

BACKGROUND: It is well known that lead exposure induces neurotoxic effects, which can result in a variety of neurocognitive dysfunction. Especially, occupational lead exposures in adults are associated with decreases in cognitive performance including working memory. Despite recent advances in human neuroimaging techniques, the neural correlates of lead-exposed cognitive impairment remain unclear. Therefore, this study was aimed to compare the neural activations in relation to working memory function between the lead-exposed subjects and healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-one lead-exposed subjects and 34 healthy subjects performed an n-back memory task during MRI scan. We performed fMRI using the 1-back and 2-back memory tasks differing in cognitive demand. Functional MRI data were analyzed using within- and between-group analysis. We found that the lead-exposed subjects showed poorer working memory performance during high memory loading task than the healthy subjects. In addition, between-group analyses revealed that the lead-exposed subjects showed reduced activation in the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, pre supplementary motor areas, and inferior parietal cortex. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that functional abnormalities in the frontoparietal working memory network might contribute to impairments in maintenance and manipulation of working memory in the lead-exposed subjects.

Combined information from resting-state functional connectivity and passive movements with functional magnetic resonance imaging differentiates fast late-onset motor recovery from progressive recovery in hemiplegic stroke patients: a pilot study.

OBJECTIVE: To investigate the value of combining information from resting-state functional connectivity and passive movements, measured with functional magnetic resonance imaging (fMRI), in acute stroke patients with severe motor impairment. SUBJECTS: Eight patients with severe left upper limb motor impairment underwent a passive movement task with fMRI and resting-state fMRI, 3 weeks following stroke onset. According to the patterns of motor recovery, patients were divided into groups with, respectively, good or poor motor recovery. Patients with good recovery were further divided into two subgroups: progressive and fast late-onset motor recovery. METHOD: Activation and deactivation maps from a passive movement task with fMRI were obtained. Interhemispheric connectivity analysis was conducted using resting-state fMRI. RESULTS: Interhemispheric connectivity score in patients with progressive motor recovery was much greater than the scores in patients with fast late-onset and poor motor recovery. For passive movement, patients with progressive recovery exhibited activation in the ipsilesional sensorimotor area and no deactivation in the contralesional sensorimotor area. Patients with fast late-onset motor recovery showed strong deactivation in both sensorimotor areas. Patients with poor recovery showed no activation or deactivation in either of the sensorimotor areas. CONCLUSION: Interhemispheric connectivity alone is not enough to predict delayed motor recovery.

Decreased brain volumes in manganese-exposed welders.

BACKGROUND: A great deal of research has been devoted to identifying subclinical functional brain abnormalities in manganese (Mn)-exposed welders. However, no previous study has investigated morphological brain abnormalities, such as changes in brain volume, in welders. This study evaluates morphological changes in brain volume among welders, and investigates the relationship between structural brain abnormalities and subclinical dysfunction in this population. METHODS: We used voxel-based morphometry (VBM) to assess differences in gray and white matter brain volumes between 40 welders with chronic Mn exposure and 26 age-matched control subjects. Correlation analyses were used to investigate the relationship between brain volume changes and decreased performance on neurobehavioral tests. RESULTS: Brain volumes in the globus pallidus and cerebellar regions were significantly diminished in welders with chronic Mn exposure compared to controls (FDR-corrected P<0.05). These changes in brain volume were negatively correlated with cognitive performance and grooved pegboard scores. CONCLUSION: There are measurable brain volume reductions in the globus pallidus and cerebellum of welders chronically exposed to Mn, and these volume reductions correlate with cognitive and motor neurobehavioral deficits. Our findings therefore indicate that volumetric measurement could be a useful subclinical marker among welders that show no signs of manganism.

Intratympanic manganese administration revealed sound intensity and frequency dependent functional activity in rat auditory pathway.

The cochlear plays a vital role in the sense and sensitivity of hearing; however, there is currently a lack of knowledge regarding the relationships between mechanical transduction of sound at different intensities and frequencies in the cochlear and the neurochemical processes that lead to neuronal responses in the central auditory system. In the current study, we introduced manganese-enhanced MRI (MEMRI), a convenient in vivo imaging method, for investigation of how sound, at different intensities and frequencies, is propagated from the cochlear to the central auditory system. Using MEMRI with intratympanic administration, we demonstrated differential manganese signal enhancements according to sound intensity and frequencies in the ascending auditory pathway of the rat after administration of intratympanic MnCl2.Compared to signal enhancement without explicit sound stimuli, auditory structures in the ascending auditory pathway showed stronger signal enhancement in rats who received sound stimuli of 10 and 40 kHz. In addition, signal enhancement with a stimulation frequency of 40 kHz was stronger than that with 10 kHz. Therefore, the results of this study seem to suggest that, in order to achieve an effective response to high sound intensity or frequency, more firing of auditory neurons, or firing of many auditory neurons together for the pooled neural activity is needed.

Carbon-coated iron oxide nanoparticles as contrast agents in magnetic resonance imaging.

Coprecipitated ferrite nanoparticles were coated with carbon using a hydrothermal method. From transmission electron microscope pictures, we could see that the coated iron oxide nanoparticles were spherical in shape with an average diameter of 90 nm. The strong bonding of carbon on the nanoparticle surfaces was checked by noting the C = O and C = C vibrations in Fourier transform infrared spectra. The spin-lattice relaxation process [T1] and spin-spin relaxation process [T2] relaxivities of hydrogen protons in the aqueous solution of coated nanoparticles were determined to be 1.139 (mM·s)-1 and 1.115 (mM·s)-1, respectively. These results showed that the carbon-coated iron oxide nanoparticles are applicable as both T1 and T2 contrast agents in magnetic resonance imaging.PACS: 81.05.y; 76.60.Es; 61.46; 75.50.k; 87.61.

Paramagnetic dysprosium oxide nanoparticles and dysprosium hydroxide nanorods as T2 MRI contrast agents.

We report here paramagnetic dysprosium nanomaterial-based T(2) MRI contrast agents. A large r(2) and a negligible r(1) is an ideal condition for T(2) MR imaging. At this condition, protons are strongly and nearly exclusively induced for T(2) MR imaging. The dysprosium nanomaterials fairly satisfy this because they are found to possess a decent r(2) but a negligible r(1) arising from L + S state 4f-electrons in Dy(III) ion ((6)H(15/2)). Their r(2) will also further increase with increasing applied field because of unsaturated magnetization at room temperature. Therefore, MR imaging and various physical properties of the synthesized d-glucuronic acid coated ultrasmall dysprosium oxide nanoparticles (d(avg) = 3.2 nm) and dysprosium hydroxide nanorods (20 × 300 nm) are investigated. These include hydrodynamic diameters, magnetic properties, MR relaxivities, cytotoxicities, and 3 tesla in vivo T(2) MR images. Here, MR imaging properties of dysprosium hydroxide nanorods have not been reported so far. These two samples show r(2)s of 65.04 and 181.57 s(-1)mM(-1), respectively, with negligible r(1)s at 1.5 tesla and at room temperature, no in vitro cytotoxicity up to 100 µM Dy, and clear negative contrast enhancements in 3 tesla in vivo T(2) MR images of a mouse liver, which will be even more improved at higher MR fields. Therefore, d-glucuronic acid coated ultrasmall dysprosium oxide nanoparticles with renal excretion can be a potential candidate as a sensitive T(2) MRI contrast agent at MR field greater than 3 tesla.

The effect of static magnetic fields on the aggregation and cytotoxicity of magnetic nanoparticles.

Biomedical applications of magnetic nanoparticles (MNP), including superparamagnetic nanoparticles, have expanded dramatically in recent years. Systematic and standardized cytotoxicity assessment to ensure the biosafety and biocompatibility of those applications is compulsory. We investigated whether exposure to static magnetic field (SMF) from e.g. magnetic resonance imaging (MRI) could affect the cytotoxicity of superparamagnetic iron oxide (SPIO) nanoparticles using mouse hepatocytes and ferucarbotran, a liver-selective MRI contrast agent as a model system. We show that while the SPIO satisfied the conventional cytotoxicity assessment, clinical doses combined with SMF exposure exerts synergistic adverse effects such as reduced cell viability, apoptosis, and cell cycle aberrations on hepatocytes in vitro and in vivo. Concomitant treatments with the SPIO and SMF generated SPIO aggregates, which demonstrated enhanced cellular uptake, was sufficient to induce the cytotoxicity without further SMF, emphasizing that the SPIO aggregates were the predominant source of the cytotoxicity. Interestingly, the apoptotic effect was dependent on levels of reactive oxygen species (ROS) and SPIO uptake while the reduced cell viability was independent of these factors. Moreover, long-term monitoring showed a significant increase in multinuclear giant cells in the cells concomitantly treated with the SPIO and SMF compared with the control. The results demonstrate that the SPIO produces unidentified cytotoxicity on liver in the presence of SMF and the SPIO aggregates predominantly exert the effect. Since aggregation of MNP in biological milieu in the presence of strong SMF is inevitable, a fundamentally different approach to surface fabrication is essential to increase the biocompatibility of MNP.

A facile synthesis, in vitro and in vivo MR studies of d-glucuronic acid-coated ultrasmall Ln2O3 (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles as a new potential MRI contrast agent.

A facile one-pot synthesis of d-glucuronic acid-coated ultrasmall Ln(2)O(3) (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles is presented. Their water proton relaxivities were studied to address their possibility as a new potential MRI contrast agent. We focused on the d-glucuronic acid-coated ultrasmall Dy(2)O(3) nanoparticle because it showed the highest r(2) relaxivity among studied nanoparticles. Its performance as a T(2) MRI contrast agent was for the first time proved in vivo through its 3 T T(2) MR images of a mouse, showing that it can be further exploited for the rational design of a new T(2) MRI contrast agent at high MR fields.