Manganese-Enhanced Magnetic Resonance Imaging and Studies of Rat Behavior: Transient Motor Deficit in Skilled Reaching, Rears, and Activity in Rats After a Single Dose of MnCl2.

Manganese-enhanced magnetic resonance imaging (MEMRI) has been suggested to be a useful tool to visualize and map behavior-relevant neural populations at large scale in freely behaving rodents. A primary concern in MEMRI applications is Mn2+ toxicity. Although a few studies have specifically examined toxicity on gross motor behavior, Mn2+ toxicity on skilled motor behavior was not explored. Thus, the objective of this study was to combine manganese as a functional contrast agent with comprehensive behavior evaluation. We evaluated Mn2+ effect on skilled reach-to-eat action, locomotion, and balance using a single pellet reaching task, activity cage, and cylinder test, respectively. The tests used are sensitive to the pathophysiology of many neurological and neurodegenerative disorders of the motor system. The behavioral testing was done in combination with a moderate dose of manganese. Behavior was studied before and after a single, intravenous infusion of MnCl2 (48 mg/kg). The rats were imaged at 1, 3, 5, 7, and 14 days following infusion. The results show that MnCl2 infusion resulted in detectable abnormalities in skilled reaching, locomotion, and balance that recovered within 3 days compared with the infusion of saline. Because some tests and behavioral measures could not detect motor abnormalities of skilled movements, comprehensive evaluation of motor behavior is critical in assessing the effects of MnCl2. The relaxation mapping results suggest that the transport of Mn2+ into the brain is through the choroid plexus-cerebrospinal fluid system with the primary entry point and highest relaxation rates found in the pituitary gland. Relaxation rates in the pituitary gland correlated with measures of motor skill, suggesting that altered motor ability is related to the level of Mn circulating in the brain. Thus, combined MEMRI and behavioral studies that both achieve adequate image enhancement and are also free of motor skills deficits are difficult to achieve using a single systemic dose of MnCl2.

Altered brain morphology and functional connectivity reflect a vulnerable affective state after cumulative multigenerational stress in rats.

Prenatal stress is a risk factor for abnormal neuroanatomical, cognitive, behavioral and mental health outcomes with potentially transgenerational consequences. Females in general seem more resilient to the effects of prenatal stress than males. Here, we examined if repeated stress across generations may diminish stress resiliency and cumulatively enhance the susceptibility for adverse health outcomes in females. Pregnant female rats of three successive generations were exposed to stress from gestational days 12-18 to generate multigenerational prenatal stress (MPS) in the maternal lineage. Stress response was measured by plasma corticosterone levels and open-field exploration in each generation. Neuromorphological consequences of MPS were investigated in the F3 generation using in vivo manganese-enhanced magnetic resonance imaging (MEMRI), T2-relaxometry, and cytoarchitectonics in relation to candidate gene expression involved in brain plasticity and mental health. Each additional generation of prenatal stress incrementally elevated hypothalamic-pituitary-adrenal axis activation, anxiety-like and aversive behaviors in adult female offspring. Elevated stress responses in the MPS F3 generation were accompanied by reduced neural density in prefrontal cortex, hippocampus and whole brain along with altered brain activation patterns in in vivo MEMRI. MPS increased ephrin receptor A5 (Epha5), neuronal growth regulator (Negr1) and synaptosomal-associated protein 25 (Snap25) gene expression and reduced fibroblast growth factor 12 (Fgf12) in prefrontal cortex. These genes regulate neuronal maturation, arborization and synaptic plasticity and may explain altered brain cytoarchitectonics and connectivity. These findings emphasize that recurrent stress across generations may cumulatively increase stress vulnerability and the risk of adverse health outcomes through perinatal programing in females.

Both compensation and recovery of skilled reaching following small photothrombotic stroke to motor cortex in the rat.

Large lesions produced by stroke to the forelimb region of motor cortex of the rat feature post-stroke improvement that in the main is due to compensation. The present study describes both recovery and compensation of forelimb use in a reach-to-eat (skilled reaching) task following small photothrombotic stroke. The rats were pretrained before stroke, and then assessed using endpoint measures and biometric movement analysis during rehabilitation in the acute and chronic post-stroke periods. Histological and MRI analysis indicated that the stroke consisted of a small lesion surrounded by cortex featuring scattered cell loss, likely of the large pyramidal cells that characterize the forelimb region of motor cortex. The stroke reduced reaching success, especially on the most demanding measure of success on first reach attempts, in the acute period, but with rehabilitation, performance returned to pre-stroke levels. Reach movements as assessed by biometric measures were severely impaired acutely but displayed significant recovery chronically although this recovery was not complete. The results suggest that not only do rats show post-stroke compensation in skilled reaching but they can also display functional recovery. It is suggested that recovery is mediated by the spared neurons in the peri-infarct region of forelimb motor cortex. The results demonstrate the utility of a small lesion model for studying post-stroke neural and behavioral change and support the view that optimal post-stroke treatment should be directed toward limiting tissue loss.

Observation of satellite signals due to scalar coupling to spin-1/2 isotopes in solid-state nuclear magnetic resonance spectroscopy.

A method is introduced to select the signal from a spin-1/2 nucleus I specifically bound to another spin-1/2 nucleus S for solid-state magic angle spinning nuclear magnetic resonance (NMR) spectroscopy via correlation through the heteronuclear J coupling. This experiment is analogous to the bilinear rotation decoupling (BIRD) sequence in liquid-state NMR spectroscopy which selects for signals from 1H directly bound to 13C. The spin dynamics of this modified BIRD experiment is described using the product-operator formalism, where experimental considerations such as rotor synchronization and the effect of large chemical shielding anisotropies on I and S are discussed. Two experiments are proposed that accommodate large chemical shielding anisotropies on S: (1) by stepping the inversion pulse frequency through the entire S spectral range or (2) by adiabatically inverting the S spins. Both these experiments are shown to successfully select the signal of 19F bound to 129Xe in XeF+ salts, removing the contributions from isotopomers containing non-spin-1/2 Xe isotopes. The feasibility in obtaining isotope-selective 19F spectra of inorganic fluoride compounds is discussed, and further modifications are proposed to expand the application to other chemical systems.

Two-compartment radial diffusive exchange analysis of the NMR lineshape of (129)Xe dissolved in a perfluorooctyl bromide emulsion.

Hyperpolarized (129)Xe (xenon) gas dissolved in a perfluorooctyl bromide (PFOB) emulsion stabilized with egg yolk phospholipid (EYP) is a possible contrast agent for quantitative blood flow measurements using magnetic resonance imaging. The NMR line shape of xenon dissolved in PFOB emulsion depends strongly on the exchange of spins between PFOB and water. The exchange in this system depends on three factors: the geometrical factors (i.e., droplet size and surrounding water volume), the permeability of the EYP monolayer surrounding the droplet, and the diffusion coefficients of xenon in the two media. A theoretical model which predicts the line shape of xenon in the emulsion based on the Bloch-Torrey equations is presented. Fitting the full width at half maximum (FWHM) of the theoretical line shapes with the FWHM of the experimental spectra obtained from emulsions with different water dilutions allows estimation of the volume-weighted average diameter of the PFOB droplets (3.5+/-0.8) microm and the permeability of the EYP membrane surrounding the droplet (58+/-14) microm / s.

Passive shimming of the fringe field of a superconducting magnet for ultra-low field hyperpolarized noble gas MRI.

Hyperpolarized noble gases (HNGs) provide exciting possibilities for MR imaging at ultra-low magnetic field strengths (<0.15 T) due to the extremely high polarizations available from optical pumping. The fringe field of many superconductive magnets used in clinical MR imaging can provide a stable magnetic field for this purpose. In addition to offering the benefit of HNG MR imaging alongside conventional high field proton MRI, this approach offers the other useful advantage of providing different field strengths at different distances from the magnet. However, the extremely strong field gradients associated with the fringe field present a major challenge for imaging since impractically high active shim currents would be required to achieve the necessary homogeneity. In this work, a simple passive shimming method based on the placement of a small number of ferromagnetic pieces is proposed to reduce the fringe field inhomogeneities to a level that can be corrected using standard active shims. The method explicitly takes into account the strong variations of the field over the volume of the ferromagnetic pieces used to shim. The method is used to obtain spectra in the fringe field of a high-field (1.89 T) superconducting magnet from hyperpolarized 129Xe gas samples at two different ultra-low field strengths (8.5 and 17 mT). The linewidths of spectra measured from imaging phantoms (30 Hz) indicate a homogeneity sufficient for MRI of the rat lung.

Theoretical signal-to-noise ratio and spatial resolution dependence on the magnetic field strength for hyperpolarized noble gas magnetic resonance imaging of human lungs.

In hyperpolarized noble gas (HNG) magnetic resonance (MR) imaging, the available polarization is independent of magnetic field strength and for large radiofrequency (rf) coils, such as those used for chest imaging, the body noise becomes the primary noise source making signal-to-noise ratio (SNR) largely frequency independent at intermediate field strengths (0.1-0.5 T). Furthermore, the reduction in the transverse relaxation time, T2, of HNG in lungs with increasing field strength, results in a decrease in the achievable SNR at higher fields. In this work, the optimum field strength for HNG MR imaging was theoretically calculated in terms of both SNR and spatial resolution. SNR calculations used the principle of reciprocity and included contributions to the noise arising from both coil and sample losses in a chest-sized coil for lung imaging. The effects of susceptibility differences, transverse relaxation time, and diffusion were considered in the resolution calculations. The calculations show that the optimum field strength for HNG MR imaging of human lungs is between 0.1 and 0.6 T depending on gas type (helium or xenon) and sample size. At the field strengths currently used by conventional clinical proton MR imaging systems (1-3 T), the predicted SNR are 10%-50% lower than at the optimum field with only slightly worse spatial resolution (10%-20%). At higher fields (>3 T), however, the SNR degrades considerably reducing the achievable spatial resolution. Although HNG of the lung is still feasible at very low field strengths (<50 mT), the available SNR is much lower than at optimum fields and this reduces the achievable spatial resolution. These findings suggest that HNG imaging may be optimally performed at much lower field strengths (0.1-0.6 T) than conventional clinical proton MR imaging systems. This could considerably decrease cost, improve patient access, and reduce chemical shift and susceptibility artifacts and rf heating.

Laser-polarized 129Xe NMR at 1.88 T and 8.5 mT: a signal-to-noise ratio comparison.

The signal-to-noise ratio of nuclear magnetic resonance signals from laser-polarized 129Xe gas was investigated at 8.5 mT and compared to that of signals acquired at 1.88 T. A dedicated 8.5 mT resistive magnet was constructed and used to acquire the signals. The SNR for 1 atm of xenon gas with a polarization of 1% was measured to be 1900 at a field of 1.88 T. Under identical acquisition conditions, the SNR at 8.5 mT was about 60 (or 32 times lower). After measuring and including all of the electrical factors of the detection systems at each field strength, theory indicates the SNR value measured at 8.5m T should be about 36 times lower. Considering the widely differing frequencies and completely different detection systems the agreement is quite good and indicates that extrapolating the frequency dependence of the SNR down to very low fields does work as long as the detection system parameters are carefully accounted for. This work suggests that magnetic resonance (MR) imaging is achievable on ideal gas samples at 8.5 mT using laser-polarized 129Xe gas down to the practical resolution limit of about 0.5mm, although the SNR will be very low (approximately 1.4). The feasibility of imaging small animals at 8.5 mT is discussed and it is suggested that a field of about 50 mT is required.