Yimin Shen

Blast-induced tinnitus and hearing loss in rats: behavioral and imaging assays.

Abstract The current study used a rat model to investigate the underlying mechanisms of blast-induced tinnitus, hearing loss, and associated traumatic brain injury (TBI). Seven rats were used to evaluate behavioral evidence of tinnitus and hearing loss, and TBI using magnetic resonance imaging following a single 10-msec blast at 14 psi or 194 dB sound pressure level (SPL). The results demonstrated that the blast exposure induced early onset of tinnitus and central hearing impairment at a broad frequency range. The induced tinnitus and central hearing impairment tended to shift towards high frequencies over time. Hearing threshold measured with auditory brainstem responses also showed an immediate elevation followed by recovery on day 14, coinciding with behaviorally-measured results. Diffusion tensor magnetic resonance imaging results demonstrated significant damage and compensatory plastic changes to certain auditory brain regions, with the majority of changes occurring in the inferior colliculus and medial geniculate body. No significant microstructural changes found in the corpus callosum indicates that the currently adopted blast exposure mainly exerts effects through the auditory pathways rather than through direct impact onto the brain parenchyma. The results showed that this animal model is appropriate for investigation of the mechanisms underlying blast-induced tinnitus, hearing loss, and related TBI. Continued investigation along these lines will help identify pathology with injury/recovery patterns, aiding development of effective treatment strategies.

MRI evaluation of axonal reorganization after bone marrow stromal cell treatment of traumatic brain injury

We treated traumatic brain injury (TBI) with human bone marrow stromal cells (hMSCs) and evaluated the effect of treatment on white matter reorganization using MRI. We subjected male Wistar rats (n = 17) to controlled cortical impact and either withheld treatment (controls; n = 9) or inserted collagen scaffolds containing hMSCs (n = 8). Six weeks later, the rats were sacrificed and MRI revealed selective migration of grafted neural progenitor cells towards the white matter reorganized boundary of the TBI‐induced lesion. Histology confirmed that the white matter had been reorganized, associated with increased fractional anisotropy (FA; p < 0.01) in the recovery regions relative to the injured core region in both treated and control groups. Treatment with hMSCs increased FA in the recovery regions, lowered T2 in the core region, decreased lesion volume and improved functional recovery relative to untreated controls. Immunoreactive staining showed axonal projections emanating from neurons and extruding from the corpus callosum into the ipsilateral cortex at the boundary of the lesion. Fiber tracking (FT) maps derived from diffusion tensor imaging confirmed the immunohistological data and provided information on axonal rewiring. The apparent kurtosis coefficient (AKC) detected additional axonal remodeling regions with crossing axons, confirmed by immunohistological staining, compared with FA. Our data demonstrate that AKC, FA, FT and T2 can be used to evaluate treatment‐induced white matter recovery, which may facilitate restorative therapy in patients with TBI. Copyright

Long-term study of brain 1H-MRS study in multiple sclerosis: Effect of glatiramer acetate therapy on axonal metabolic function and feasibility of long-term 1H-MRS monitoring in multiple sclerosis

Glatiramer acetate (GA) has several putative mechanisms of action with the potential of limiting sublethal axonal injury in the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (1H‐MRS) allows in vivo examination of axonal integrity by quantifying the neuronal marker N‐acetylaspartate (NAA), often expressed as a ratio to creatine (Cr). We showed that treatment with GA led to improvement in NAA/Cr over a 2‐year period. We now report the results of this ongoing study after 4 years of annual brain 1H‐MRS examinations. Compared to baseline, at year 4, patients receiving continuous GA therapy showed a 12.7% increase in NAA/Cr and (P= .03) in the multivoxel brain volume of interest (VOI) studied and by 9.6% (P= .04) in the normal‐appearing white matter within the VOI. Three patients in the control group who began therapy with GA during the course of the study showed similar increases in NAA/Cr after the first year of therapy. These data support the long‐term effect of GA on maintaining axonal metabolic function and protection from sublethal injury as well as the feasibility of employing brain 1H‐MRS in long‐term investigative studies in MS.

A EuII-Containing Cryptate as a Redox Sensor in Magnetic Resonance Imaging of Living Tissue

The Eu(II) ion rivals Gd(III) in its ability to enhance contrast in magnetic resonance imaging. However, all reported Eu(II)-based complexes have been studied in vitro largely because the tendency of Eu(II) to oxidize to Eu(III) has been viewed as a major obstacle to in vivo imaging. Herein, we present solid- and solution-phase characterization of a Eu(II)-containing cryptate and the first in vivo use of Eu(II) to provide contrast enhancement. The results indicate that between one and two water molecules are coordinated to the Eu(II) core upon dissolution. We also demonstrate that Eu(II)-based contrast enhancement can be observed for hours in a mouse.

Aerosol delivery in ventilated newborn pigs: an MRI evaluation.

Pulmonary deposition of inhaled drugs in ventilated neonates has not been studied in vivo. The objective of this study was to evaluate pulmonary delivery of gadopentetate dimeglumine (Gd-DTPA) following nebulization in ventilated piglets using magnetic resonance imaging. Seven ventilated piglets (5 ± 2 d old, weight 1.8 ± 0.5 kg) were scanned in the Bruker/Siemens 4T magnetic resonance scanner using T1 weighted spin-echo sequence. Aerosols of Gd-DTPA were generated continuously using the MiniHeart jet nebulizer. Breath-hold coronal images were obtained before and every 10 min during aerosolized Gd-DTPA for 90 min. Signal intensity (SI) changes over the lungs, kidneys, liver, skeletal muscle, and heart were evaluated. A significant increase in SI was observed in the lungs, kidney, and liver at 10, 20, and 40 min respectively after start of aerosol. At the end of 90 min, the SI increased by 95%, 101%, and 426% over the right lung, left lung, and kidney, respectively. A much smaller increase in SI was observed over the liver. In conclusion, we have demonstrated effective pulmonary aerosol delivery within 10 min of contrast nebulization in ventilated piglets. Contrast visualization in the kidneys within 20 min of aerosol initiation reflects alveolar absorption, glomerular filtration and renal concentration.

Effects of variable blast pressures on blood flow and oxygen saturation in rat brain as evidenced using MRI

It has been recognized that primary blast waves may result in neurotrauma in soldiers in theater. A new type of contrast used in magnetic resonance imaging (MRI), susceptibility-weighted imaging (SWI), has been developed that is based on the different susceptibility levels in diverse tissues and can detect decreases in cerebral blood flow (CBF) using inferred oxygen saturation changes in tissue. In addition, a continuous arterial spin-labeled (ASL) MRI sequence was used as a direct measure of regional CBF within the brain tissue. Animals were subjected to whole-body blast exposures of various overpressures within a gas-driven shock tube. When exposed to low levels of overpressure, most rats demonstrated no obvious changes between pre- and postexposure in the conventional MR images. CBF changes measured by SWI and ASL were significantly higher for the overpressure exposed groups as compared to the sham group and tended to increase with pressure increases at the highest two pressures. In the hippocampus, all blast animals had a reduction in the CBF consistently in the range of 0-27%. In summary, low levels of primary blast pressure exposure demonstrated a significant physiologic effect to the brain up to 72 h postexposure.

Effective aerosol delivery during high-frequency ventilation in neonatal pigs

Background and objective:  Pulmonary delivery of aerosols during high‐frequency oscillatory ventilation (HFOV) has not been studied in vivo. This study investigated the pulmonary delivery of aerosolized gadopentetate dimeglumine (Gd‐DTPA) in a HFOV circuit in piglets using MRI to visualize contrast excretion in the kidneys.

Evaluation of EuII-based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

Eu(II) -based contrast agents offer physiologically relevant, metal-based redox sensing that is unachievable with Gd(III) -based contrast agents. To evaluate the in vivo contrast enhancement of Eu(II) as a function of injection type, we performed intravenous, intraperitoneal, and subcutaneous injections in mice. Our data reveal a correlation between reported oxygen content and expected rates of diffusion with the persistence of Eu(II) -based contrast enhancement. Biodistribution studies revealed europium clearance through the liver and kidneys for intravenous and intraperitoneal injections, but no contrast enhancement was observed in organs associated with clearance. These data represent a step toward understanding the behavior of Eu(II) -based complexes in vivo. Copyright

Structural Features of Europium(II)-Containing Cryptates That Influence Relaxivity

EuII -containing complexes were studied with respect to properties relevant to their use as contrast agents for magnetic resonance imaging. The influences of molecular parameters and field strength on relaxivity were studied for a series of EuII -containing cryptates and their adducts with β-cyclodextrins, poly-β-cyclodextrins, and human serum albumin. Solid- and solution-phase characterization of EuII -containing complexes is presented that demonstrates the presence of inner-sphere molecules of water. Additionally, relaxivity, water-exchange rate, rotational correlation time, and electronic relaxation times were determined using variable-temperature 17 O NMR, nuclear magnetic relaxation dispersion, and electron paramagnetic resonance spectroscopic techniques. These results are expected to be instrumental in the design of future EuII -based contrast agents.

Significant differences in proton trimethyl ammonium signals between human gastrocnemius and soleus muscle

To study the apparent heterogeneous characteristics of trimethyl ammonium (TMA) in healthy human muscles at rest, and to illustrate the importance of establishing the baseline characteristics of proton metabolites in muscles with a West Nile patient.