Faculty Bibliography

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

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.

Early life stress is a potential precursor of eventual neuropsychiatric diseases and may result in altered neurodevelopment and function of the hippocampus, which thus provides a site at which potential interventions to modify the effects of early life stress may act. In this study, Sprague-Dawley rat pups comprising male and female animals underwent maternal separation (MS) for 180 min from postnatal days (PND) 2 to 14, or were left with their dams. They subsequently received daily administration of saline (0.9%), escitalopram (10 mg/kg), or no treatment during adolescence (PND 43-60). All adult animals underwent brain magnetic resonance imaging (MRI) and bilateral hippocampal proton magnetic resonance spectroscopy ((1)H-MRS). Neither MS nor escitalopram treatment had a significant effect on hippocampal volume. Adult rats that experienced MS displayed significantly increased choline-containing compounds (Cho) and decreased N-acetylaspartate (NAA), glutamate (Glu) and Myo-inositol (MI) relative to the stable neurometabolite creatine (Cr) in hippocampus. Administration of escitalopram during adolescence could modify the alterations of NAA/Cr, Glu/Cr and MI/Cr. The effects of MS on hippocampal neurochemistry were most significant in the right hippocampus. These results indicate that MS in rats has long-term consequences on hippocampal neurochemistry reflective of neural density/functional integrity, especially on the right hippocampus, and adolescent administration with escitalopram can at least partially ameliorate these neurochemical alterations. Furthermore, these metabolite changes seem to be more sensitive indicators of the results from early life stress than volume changes.

The integrity of the neuronal connections between eye and brain plays an important role in the performance of the mammalian visual system. However, the developmental and pathophysiological mechanisms in the visual system are largely unexplored due to the lack of a sensitive technique for directly assessing both anterior and posterior visual pathways longitudinally under the same experimental conditions. This paper reviewed the recent use of magnetic resonance imaging and spectroscopic (MRI/MRS) methods (contrast-enhanced MRI, diffusion MRI, proton MRS and functional MRI) at high magnetic field strengths, for in vivo and global assessments of the structure, metabolism and function of the visual system in normal, developing and injured rodent brains. Using animal models of ocular diseases, optic neuropathies, developmental plasticity and neonatal hypoxic-ischemic brain injury, focus is put on the feasibility of MRI/MRS to evaluate axonal transport and cellular activity along segregated fibers of the visual pathways, to characterize lesion-induced neurodegeneration in the retina and the optic nerve and tract, to detect steady-state metabolite changes in the posterior visual nuclei, and blood-ocular dynamic exchanges in the eye, and to understand the neurovascular coupling and functions in the retina and the visual brain nuclei. These studies suggested the significant values of high-field multiparametric MRI/MRS for providing early diagnoses and comprehensive therapeutic strategies for promoting functional recovery upon partial vision loss.

Brain hypothermia has demonstrated pronounced neuroprotective effect in patients with cardiac arrest, ischemia and acute liver failure. However, its underlying neuroprotective mechanisms remain to be elucidated in order to improve therapeutic outcomes. Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) was performed using a 7 Tesla MRI scanner on normal Sprague-Dawley rats (N=8) in the same voxel under normothermia (36.5 degrees C) and 30min mild hypothermia (33.5 degrees C). Levels of various brain proton metabolites were compared. The level of lactate (Lac) and myo-inositol (mI) increased in the cortex during hypothermia. In the thalamus, taurine (Tau), a cryogen in brain, increased and choline (Cho) decreased. These metabolic alterations indicated the onset of a number of neuroprotective processes that include attenuation of energy metabolism, excitotoxic pathways, brain osmolytes and thermoregulation, thus protecting neuronal cells from damage. These experimental findings demonstrated that (1)H-MRS can be applied to investigate the changes of specific metabolites and corresponding neuroprotection mechanisms in vivo noninvasively, and ultimately improve our basic understanding of hypothermia and ability to optimize its therapeutic efficacy.

Recently, remarkable success has been demonstrated in using MR diffusion tensor imaging (DTI) to characterize white matter. Water diffusion in complex biological tissue microstructure is not a free or Gaussian process but is hindered and restricted, thus contradicting the basic assumption in conventional DTI that diffusion weighted signal decays with b-value in a monoexponential manner. Nevertheless, DTI by far is still the fastest and most robust protocol in routine research and clinical settings. To assess the b-value dependence of DTI indices and evaluate their sensitivities in detecting neural tissues changes, in vivo DTI data acquired from rat brains at postnatal day 13, 21 and 120 with different b-values (0.5-2.5 ms/microm(2)) and 30 gradient directions were analyzed. Results showed that the mean and directional diffusivities consistently decreased with b-value in both white and gray matters. The sensitivity of axial diffusivity (lambda(//)) in monitoring brain maturation generally decreased with b-value whereas that of radial diffusivity (lambda( perpendicular)) increased. FA generally varied less with b-value but in a manner dependent of the age and tissue type. Analysis also revealed that the FA sensitivity in detecting specific tissue changes was affected by b-value. These experimental findings confirmed the crucial effect of b-value on quantitative DTI in monitoring neural tissue alterations. They suggested that the choice of b-value in conventional DTI acquisition can be optimized for detecting neural tissue changes but shall depend on the specific tissue type and its changes or pathologies targeted, and caution must be taken in interpreting DTI indices.

The superior colliculus (SC) is a laminated subcortical structure in the mammalian midbrain, whose superficial layers receive visual information from the retina and the visual cortex. To date, its functional organization and development in the visual system remain largely unknown. This study employed blood oxygenation level-dependent (BOLD) functional MRI to evaluate the visual responses of the SC in normally developing and severe neonatal hypoxic-ischemic (HI)-injured rat brains from the time of eyelid opening to adulthood. MRI was performed to the normal animals (n=7) at postnatal days (P) 14, 21, 28 and 60. In the HI-injured group (n=7), the ipsilesional primary and secondary visual cortices were completely damaged after unilateral ligation of the left common carotid artery at P7 followed by hypoxia for 2 h, and MRI was performed at P60. Upon unilateral flash illumination, the normal contralateral SC underwent a systematic increase in BOLD signal amplitude with age especially after the third postnatal week. However, no significant difference in BOLD signal increase was found between P14 and P21. These findings implied the presence of neurovascular coupling at the time of eyelid opening, and the progressive development of hemodynamic regulation in the subcortical visual system. In the HI-injured group at P60, the BOLD signal increases in both SC remained at the same level as the normal group at P28 though they were significantly lower than the normal group at P60. These observations suggested the residual visual functions on both sides of the subcortical brain, despite the damages to the entire ipsilesional visual cortex. The results of this study constitute important evidence on the progressive maturation of visual functions and hemodynamic responses in the normal subcortical brain, and its functional plasticity upon neonatal HI injury.

Understanding the alterations of migratory activities of the endogenous neural stem/progenitor cells (NSPs) in injured developing brains is becoming increasingly imperative for curative reasons. In this study, 10-day-old neonatal rats with and without hypoxic-ischemic (HI) insult at postnatal day 7 were injected intraventricularly with micron-sized iron oxide particles (MPIOs), followed by serial high-resolution MRI at 7 T for 2 weeks. MRI findings were correlated to the histological analysis using iron staining and several immunohistochemical double staining. The results indicated that in normal and HI-injured brains the NSPs from the subventricular zone (SVZ) were labeled by MPIOs, and migrated as newly created cells (iron+/BrdU+), neuroblasts (iron+/nestin+), astrocytes or astrocytes-like progenitor cells (iron+/GFAP+), and mature neurons (iron+/NeuN+). In normal brains, the endogenous NSPs mainly exhibited a tangential pattern in both rostral and caudal directions. The NSP radial migratory pattern could be observed in some rats. In the HI-injured brains during the same developmental period, the NSPs mainly migrated towards the HI lesion sites. The tangential, rostrocaudal migrations could be observed but impaired. These findings suggest that the NSP migratory pathways in SVZ change in response to the HI insult, likely due to the self-repairing efforts known in the neonatal brains. The MRI approach demonstrated here is potentially applicable to the in vivo and longitudinal study of NSP cell activities in developing brains under normal and pathological conditions and in therapeutic interventions.

Neonatal hypoxic-ischemic encephalopathy is a major cause of brain damage in infants, and is associated with periventricular white matter injury and chronic neurological dysfunctions. However, the mechanisms of the chronic white matter injury and reorganization are still unclear. In this study, in vivo diffusion tensor imaging (DTI) was employed to evaluate the late changes of white matter microstructural integrity in the rat brains at 10 weeks after severe neonatal hypoxic-ischemic insults at postnatal day 7. In the fractional anisotropy directionality map, qualitative evaluation showed that a dorsoventrally oriented fiber bundle extended from the corpus callosum into the cyst in the anterior brain, whilst the posterior peri-infarct areas had similar fiber orientations as the contralateral internal capsule, optic tract and fimbria of hippocampus. Compared to the contralateral hemisphere, significantly higher fractional anisotropy, axial diffusivity and diffusion trace value were observed quantitatively in the distal end of the extended fiber bundle connecting the anterior and posterior white matters rostrocaudally. A significantly lower fractional anisotropy but higher axial and radial diffusivities and trace were also found in the ipsilateral corpus callosum, proximal external capsule and anterior commissure, while slightly lower fractional anisotropy and axial diffusivity were noticed in the ipsilateral internal capsule and optic nerve. It was suggested that increased fractional anisotropy, axial diffusivity and trace characterize white matter reorganization in chronic neonatal hypoxic-ischemic insults, whereas reduction in fractional anisotropy appears to characterize two types of white matter lesions, with significantly higher axial and radial diffusivities and trace being primary and slightly lower axial diffusivity being secondary. Combined with fractional anisotropy directionality map, in vivo DTI provides important indices to differentiate the chronic effects of severe neonatal hypoxic-ischemic injury and recovery globally, quantitatively and non-invasively.

PURPOSE: To evaluate the late effects of radiation-induced damages in the rat brain by means of in vivo multiparametric MRI. MATERIALS AND METHODS: The right hemibrains of seven Sprague-Dawley rats were irradiated with a highly collimated 6 MV photon beam at a single dose of approximately 28 Gy. Diffusion tensor imaging (DTI), proton MR spectroscopy ((1)H-MRS), T2-weighted imaging, and T1-weighted imaging were performed to the same animals 12 months after radiation treatment. RESULTS: Compared with the contralateral side, a significantly higher percentage decrease in fractional anisotropy was observed in the ipsilateral fimbria of hippocampus (29%) than the external capsule (8%) in DTI, indicating the selective vulnerability of fimbria to radiation treatment. Furthermore, in (1)H-MRS, significantly higher choline, glutamate, lactate, and taurine peaks by 24%, 25%, 87%, and 58%, respectively, were observed relative to creatine in the ipsilateral brain. Postmortem histology confirmed these white matter degradations as well as glial fibrillary acidic protein and glutamine synthetase immunoreactivity increase in the ipsilateral brain. CONCLUSION: The microstructural and metabolic changes in late radiation-induced brain injuries were documented in vivo. These multiparametric MRI measurements may help understand the white matter changes and neurotoxicity upon radiation treatment in a single setting.