Ceftriaxone improves impairments in synaptic plasticity and cognitive behavior in APP/PS1 mouse model of Alzheimer's disease by inhibiting extrasynaptic NMDAR-STEP61 signaling.

Abnormal activation of the extrasynaptic N-methyl-d-aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by upregulating glutamate transporter-1 and promoting the glutamate-glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive-behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno-associated virus (AAV)-striatal enriched tyrosine phosphatase 61 (STEP61 ) and AAV-STEP61 -shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long-term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m-calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef-induced inhibition of the expressions of GluN2B, GluN2BTyr1472 , and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef-induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.

Ceftriaxone ameliorates hippocampal synapse loss by inhibiting microglial/macrophages activation in glial glutamate transporter-1 dependent manner in the APP/PS1 mouse model of Alzheimer's disease.

Synapse loss is a major contributor to cognitive dysfunction in Alzheimer's disease (AD). Impairments in the expression and/or glutamate uptake activity of glia glutamate transporter-1 (GLT-1) contribute to synapse loss in AD. Hence, targeting the restoration of GLT-1 activity may have potential for alleviating synapse loss in AD. Ceftriaxone (Cef) can upregulate the expression and glutamate uptake activity of GLT-1 in many disease models, including those for AD. The present study investigated the effects of Cef on synapse loss and the role of GLT-1 using APP/PS1 transgenic and GLT-1 knockdown APP/PS1 AD mice. Furthermore, the involvement of microglia in the process was investigated due to its important role in synapse loss in AD. We found that Cef treatment significantly ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice, evidenced by an increased dendritic spine density, decreased dendritic beading density, and upregulated levels of postsynaptic density protein 95 (PSD95) and synaptophysin. The effects of Cef were suppressed by GLT-1 knockdown in GLT-1+/-/APP/PS1 AD mice. Simultaneously, Cef treatment inhibited ionized calcium binding adapter molecule 1 (Iba1) expression, decreased the proportion of CD11b+CD45hi cells, declined interleukin-6 (IL-6) content, and reduced the co-expression of Iba1 with PSD95 or synaptophysin in APP/PS1 AD mice. In conclusion, Cef treatment ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice in a GLT-1-dependent manner, and the inhibitory effect of Cef on the activation of microglia/macrophages and their phagocytosis for synaptic elements contributed to the mechanism.

Neonatal isovaleric acidemia in China: A case report and review of literature.

BACKGROUND: Isovaleric acidemia (IVA) is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase (IVD). Its morbidity is low, but mortality is high. There is no effective cure for this disease. Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality. Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease. CASE SUMMARY: A 12-day-old male neonate with "poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h" was hospitalized. The patient was the first child of nonconsanguineous ethnic Chinese parents. He was delivered by cesarean section due to breech position at 39 + 1 wk of gestation with a birth weight of 3.27 kg. Initially, he suffered from dyspnea and rhinobyon, and at 10 d after birth the patient suddenly developed poor feeding, low response, lethargy and seizures. Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine. The patient had an acute episode of IVA causing severe metabolic stress and eventually died. CONCLUSION: A new case of an IVA patient carrying c.1193G>A (p.Arg398Gln) and c.1208A>G (p.Try403Cys) mutations is reported in China.

Activation of p38 MAPK participates in the sulbactam-induced cerebral ischemic tolerance mediated by glial glutamate transporter-1 upregulation in rats.

Our previous studies have shown that sulbactam can play a neuroprotection role in hippocampal neurons by upregulating the expression and function of glial glutamate transporter-1 (GLT-1) during ischemic insult. Here, using rat global cerebral ischemia model, we studied in vivo the role of p38 mitogen-activated protein kinases (MAPK) in the sulbactam-induced GLT-1 upregulation and neuroprotection against ischemia. The hippocampal CA1 field was selected as observing target. The expressions of phosphorylated-p38 MAPK and GLT-1 were assayed with western blot analysis and immunohistochemistry. The condition of delayed neuronal death (DND) was assayed with neuropathological evaluation under thionin staining. It was shown that administration of sulbactam protected CA1 hippocampal neurons against ischemic insult accompanied with significantly upregulation in the expressions of phosphorylated-p38 MAPK and GLT-1. The time course analysis showed that sulbactam activated p38 MAPK before the GLT-1 upregulation in either normal or global cerebral ischemic rats. Furthermore, inhibiting p38 MAPK activation by SB203580 blocked the GLT-1 upregulation and neuroprotection induced by sulbactam. The above results suggested that p38 MAPK, at least partly, participated in the sulbactam-induced brain tolerance to ischemia mediated by GLT-1 upregulation in rats.

Volumetric imaging of myelin in vivo using 3D inversion recovery-prepared ultrashort echo time cones magnetic resonance imaging.

Direct myelin imaging is promising for characterization of multiple sclerosis (MS) brains at diagnosis and in response to therapy. In this study, a 3D inversion recovery-prepared ultrashort echo time cones (IR-UTE-Cones) sequence was used for both morphological and quantitative imaging of myelin on a clinical 3 T scanner. Myelin powder phantoms with different myelin concentrations were imaged with the 3D UTE-Cones sequence and it showed a strong correlation between concentrations and UTE-Cones signals, demonstrating the ability of the UTE-Cones sequence to directly image myelin in the brain. Quantitative myelin imaging with multi-echo IR-UTE-Cones sequences show similar T2 * values for a D2 O-exchanged myelin phantom (T2 * = 0.33 ± 0.04 ms), ex vivo brain specimens (T2 * = 0.20 ± 0.04 ms) and in vivo healthy volunteers (T2 * = 0.254 ± 0.023 ms), further confirming the feasibility of 3D IR-UTE-Cones sequences for direct myelin imaging in vivo. In ex vivo MS brain study, signal loss is observed in MS lesions, which was confirmed with histology. For the in vivo study, the lesions in MS patients also show myelin signal loss using the proposed direct myelin imaging method, demonstrating the clinical potential for MS diagnosis. Furthermore, the measured IR-UTE-Cones signal intensities show a significant difference between normal-appearing white matter in MS patients and normal white matter in volunteers, which cannot be found in clinical used T2 -FLAIR sequences. Thus, the proposed 3D IR-UTE-Cones sequence showed clinical potential for MS diagnosis with the capability of direct myelin detection of the whole brain.

The effects of sub-anesthetic ketamine plus ethanol on behaviors and apoptosis in the prefrontal cortex and hippocampus of adolescent rats.

Ketamine has become increasingly popular in adolescent drug abusers worldwide. Meanwhile, alcohol is usually used by ketamine users. However, little work has been conducted to examine the chronic combined effects of ketamine and ethanol on adolescent brain. Here we probed into the effects of chronic administration of ketamine at recreational doses alone or combined with ethanol on behaviors and neuron damage in an adolescent rat model. 28-day old rats were treated with either 20 or 30 mg/kg ketamine plus or not plus 10% ethanol daily for 21 days. Depressive like behaviors, anxiety like behavior and memory impairment were tested using open field test, forced swimming test, elevated plus maze and Morris water maze. Apoptosis in prefrontal cortex (PFC) and hippocampus (HIP) were determined by the TdT-mediated dUTP Nick-End Labeling (TUNEL) and protein and mRNA levels of caspase-3, Bax and Bcl-2. Results show that co-application of ketamine and ethanol significantly increased immobility time in the forced swimming test, up-regulated TUNEL positive cells and both protein and mRNA expressions of caspase-3 and Bax, compared with the control group and ketamine and ethanol use alone groups in the PFC, but not in the HIP. Our study suggests that chronic co-administration of ketamine and ethanol results in depressive-like behavior and the caspase-dependent apoptosis in the PFC of adolescent rats' brains.

Feasibility of quantitative ultrashort echo time (UTE)-based methods for MRI of peripheral nerve.

Peripheral nerves are a composite tissue consisting of neurovascular elements packaged within a well-organized extracellular matrix. Their composition, size, and anatomy render nerves a challenging medical imaging target. In contrast to morphological MRI, which represents the predominant approach to nerve imaging, quantitative MRI sequences can provide information regarding tissue composition. Here, we applied standard clinical Carr-Purcell-Meiboom-Gill (CPMG) and experimental three-dimensional (3D) ultrashort echo time (UTE) Cones sequences for quantitative nerve imaging including T2 measurement with single-component analysis, T2 * measurement with single-component and bi-component analyses, and magnetization transfer ratio (MTR) analysis. We demonstrated the feasibility and the high quality of single-component T2 *, bi-component T2 *, and MTR approaches to analyze nerves imaged with clinically deployed 3D UTE Cones pulse sequences. For 24 single fascicles from eight nerves, we measured a mean single-component T2 * of 22.6 ±8.9 ms, and a short T2 * component (STC) with a mean T2 * of 1.7 ±1.0 ms and a mean fraction of (6.74 ±4.31)% in bi-component analysis. For eight whole nerves, we measured a mean single-component T2 * of 16.7 ±2.2 ms, and an STC with a mean T2 * of 3.0 ±1.0 ms and a mean fraction of (15.56 ±7.07)% in bi-component analysis. For nine fascicles from three healthy nerves, we measured a mean MTR of (25.2 ±1.9)% for single fascicles and a mean MTR of (23.6 ±0.9)% for whole nerves. No statistically significant correlation was observed between any MRI parameter and routine histological outcomes, perhaps due to the small sample size and lack of apparent sample pathology. Overall, we have successfully demonstrated the feasibility of measuring quantitative MR outcomes ex vivo, which might reflect features of nerve structure and macromolecular content. These methods should be validated comprehensively on a larger and more diverse set of nerve samples, towards the interpretation of in vivo outcomes. These approaches have new and broad implications for the management of nerve disease, injury, and repair.

[Influence of acute pancreatitis in pregnancy on pregnancy outcomes and neonates].

OBJECTIVE: To study the influence of acute pancreatitis in pregnancy (APIP) on pregnancy outcomes and neonates. METHODS: A retrospective analysis was performed for 33 APIP patients and 31 neonates born alive. RESULTS: Of the 33 APIP patients, 26 (79%) developed APIP in the late pregnancy. Fourteen (45%) patients had hyperlipidemic APIP, 13 (42%) had biliary APIP, and 4 (13%) had other types of APIP. According to the severity, 22 (67%) were mild APIP, 5 (15%) were moderate APIP, and 6 were severe APIP. None of the 33 APIP patients died. Among the 20 patients with term delivery, 11 underwent termination of pregnancy; among the 10 patients with preterm delivery, 9 underwent termination of pregnancy; two patients experienced intrauterine fetal death, and one experienced abortion during the second trimester. Among the 31 neonates born alive (two of them were twins), 1 (3%) died, 12 (39%) experienced neonatal hyperbilirubinemia, 8 (26%) had neonatal hypoglycemia, 6 (19%) had neonatal respiratory distress syndrome, 5 (16%) experienced infectious diseases, and 2 (6%) experienced intracranial hemorrhage. The hyperlipidemic APIP group had a higher percentage of patients undergoing termination of pregnancy than the biliary APIP and other types of APIP groups (P<0.05). The incidence rate of preterm infants in the moderate APIP was higher than in the mild and severe APIP groups (P<0.05). The mean birth weights of neonates were the lowest in the moderate APIP group. The incidence rates of neonatal respiratory distress syndrome, intracranial hemorrhage, and infectious disease were the lowest in the mild APIP group (P<0.05). CONCLUSIONS: APIP can lead to adverse pregnancy outcomes and neonatal diseases, which are associated with the severity of pancreatitis.

Yet more evidence that myelin protons can be directly imaged with UTE sequences on a clinical 3T scanner: Bicomponent T2* analysis of native and deuterated ovine brain specimens.

PURPOSE: UTE sequences with a minimal nominal TE of 8 µs have shown promise for direct imaging of myelin protons (T2 , < 1 ms). However, there is still debate about the efficiency of 2D slice-selective UTE sequences in exciting myelin protons because the half excitation pulses used in these sequences have a relatively long duration (e.g., 0.3-0.6 ms). Here, we compared UTE and inversion-recovery (IR) UTE sequences used with either hard or half excitation pulses (durations 32 µs or 472 µs, respectively) for imaging myelin in native and deuterated ovine brain at 3T. METHODS: Freshly frozen ovine brains were dissected into ∼2 mm-thick pure white matter and ∼3 to 8 mm-thick cerebral hemisphere specimens, which were imaged before and/or after different immersion time in deuterium oxide. RESULTS: Bicomponent T2* analysis of UTE signals obtained with hard excitation pulses detected an ultrashort T2 component (STC) fraction (fS ) of 0% to 10% in native specimens, and up to ∼86% in heavily deuterated specimens. fS values were significantly affected by the TIs used in IR-UTE sequences with either hard or half excitation pulses in native specimens but not in heavily deuterated specimens. The STC T2* was in the range of 150 to 400 µs in all UTE and IR-UTE measurements obtained with either hard or half excitation pulses. CONCLUSION: Our results further support myelin protons as the major source of the ultrashort T2* signals seen on IR-UTE images and demonstrate the potential of IR-UTE sequences with half excitation pulses for directly imaging myelin using clinical scanners. Magn Reson Med 80:538-547, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Inversion recovery ultrashort echo time imaging of ultrashort T2 tissue components in ovine brain at 3 T: a sequential D2 O exchange study.

Inversion recovery ultrashort echo time (IR-UTE) imaging holds the potential to directly characterize MR signals from ultrashort T2 tissue components (STCs), such as collagen in cartilage and myelin in brain. The application of IR-UTE for myelin imaging has been challenging because of the high water content in brain and the possibility that the ultrashort T2 * signals are contaminated by water protons, including those associated with myelin sheaths. This study investigated such a possibility in an ovine brain D2 O exchange model and explored the potential of IR-UTE imaging for the quantification of ultrashort T2 * signals in both white and gray matter at 3 T. Six specimens were examined before and after sequential immersion in 99.9% D2 O. Long T2 MR signals were measured using a clinical proton density-weighted fast spin echo (PD-FSE) sequence. IR-UTE images were first acquired with different inversion times to determine the optimal inversion time to null the long T2 signals (TInull ). Then, at this TInull , images with echo times (TEs) of 0.01-4 ms were acquired to measure the T2 * values of STCs. The PD-FSE signal dropped to near zero after 24 h of immersion in D2 O. A wide range of TInull values were used at different time points (240-330 ms for white matter and 320-350 ms for gray matter at TR = 1000 ms) because the T1 values of the long T2 tissue components changed significantly. The T2 * values of STCs were 200-300 µs in both white and gray matter (comparable with the values obtained from myelin powder and its mixture with D2 O or H2 O), and showed minimal changes after sequential immersion. The ultrashort T2 * signals seen on IR-UTE images are unlikely to be from water protons as they are exchangeable with deuterons in D2 O. The source is more likely to be myelin itself in white matter, and might also be associated with other membranous structures in gray matter.

Longitudinal Assessments of Normal and Perilesional Tissues in Focal Brain Ischemia and Partial Optic Nerve Injury with Manganese-enhanced MRI.

Although manganese (Mn) can enhance brain tissues for improving magnetic resonance imaging (MRI) assessments, the underlying neural mechanisms of Mn detection remain unclear. In this study, we used Mn-enhanced MRI to test the hypothesis that different Mn entry routes and spatiotemporal Mn distributions can reflect different mechanisms of neural circuitry and neurodegeneration in normal and injured brains. Upon systemic administration, exogenous Mn exhibited varying transport rates and continuous redistribution across healthy rodent brain nuclei over a 2-week timeframe, whereas in rodents following photothrombotic cortical injury, transient middle cerebral artery occlusion, or neonatal hypoxic-ischemic brain injury, Mn preferentially accumulated in perilesional tissues expressing gliosis or oxidative stress within days. Intravitreal Mn administration to healthy rodents not only allowed tracing of primary visual pathways, but also enhanced the hippocampus and medial amygdala within a day, whereas partial transection of the optic nerve led to MRI detection of degrading anterograde Mn transport at the primary injury site and the perilesional tissues secondarily over 6 weeks. Taken together, our results indicate the different Mn transport dynamics across widespread projections in normal and diseased brains. Particularly, perilesional brain tissues may attract abnormal Mn accumulation and gradually reduce anterograde Mn transport via specific Mn entry routes.

Auditory midbrain processing is differentially modulated by auditory and visual cortices: An auditory fMRI study.

The cortex contains extensive descending projections, yet the impact of cortical input on brainstem processing remains poorly understood. In the central auditory system, the auditory cortex contains direct and indirect pathways (via brainstem cholinergic cells) to nuclei of the auditory midbrain, called the inferior colliculus (IC). While these projections modulate auditory processing throughout the IC, single neuron recordings have samples from only a small fraction of cells during stimulation of the corticofugal pathway. Furthermore, assessments of cortical feedback have not been extended to sensory modalities other than audition. To address these issues, we devised blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) paradigms to measure the sound-evoked responses throughout the rat IC and investigated the effects of bilateral ablation of either auditory or visual cortices. Auditory cortex ablation increased the gain of IC responses to noise stimuli (primarily in the central nucleus of the IC) and decreased response selectivity to forward species-specific vocalizations (versus temporally reversed ones, most prominently in the external cortex of the IC). In contrast, visual cortex ablation decreased the gain and induced a much smaller effect on response selectivity. The results suggest that auditory cortical projections normally exert a large-scale and net suppressive influence on specific IC subnuclei, while visual cortical projections provide a facilitatory influence. Meanwhile, auditory cortical projections enhance the midbrain response selectivity to species-specific vocalizations. We also probed the role of the indirect cholinergic projections in the auditory system in the descending modulation process by pharmacologically blocking muscarinic cholinergic receptors. This manipulation did not affect the gain of IC responses but significantly reduced the response selectivity to vocalizations. The results imply that auditory cortical gain modulation is mediated primarily through direct projections and they point to future investigations of the differential roles of the direct and indirect projections in corticofugal modulation. In summary, our imaging findings demonstrate the large-scale descending influences, from both the auditory and visual cortices, on sound processing in different IC subdivisions. They can guide future studies on the coordinated activity across multiple regions of the auditory network, and its dysfunctions.

Effect of ischemic postconditioning on cerebral edema and the AQP4 expression following hypoxic-eschemic brain damage in neonatal rats.

BACKGROUND: A rat model for neonatal hypoxic-ischemic brain damage (HIBD) was established to observe the effect of ischemic postconditioning (IPostC) on cerebral edema and the AQP4 expression following HIBD and to verify the neuroprotection of IPostC and the relationship between changes of AQP4 expression and cerebral edema. METHODS: Water content was measured with dry-wet method, and AQP4 transcription and the protein expression of the lesions were detected with real-time PCR and immunohistochemistry staining, respectively. RESULTS: Within 6-48 hours, the degree of ipsilateral cerebral edema was significantly lower in IPostC-15 s/15 s group than in HIBD group. Similar to the HIBD group, the AQP4 transcription and expression in the IPostC group showed a downward and then upward trend. But the expression was still more evident in the HIBD group than in the IPostC-15 s/15 s group. From 24 to 48 hours, IPostC-15 s/15 s decreased the slowing down expression of AQP4. CONCLUSION: IPostC has neuroprotective effect on neonatal rats with HIBD and it may relieve cerebral edema by regulating the expression of AQP4.

Diffusion magnetic resonance monitors intramyocellular lipid droplet size in vivo.

PURPOSE: Intramyocellular lipid (IMCL) droplets are dynamic organelles whose morphology reflects their vital roles in lipid synthesis, usage, and storage in muscle energy metabolism. To develop noninvasive means to measure droplet microstructure in vivo, we investigated the molecular diffusion behavior of IMCL with diffusion magnetic resonance spectroscopy. METHODS: Using extremely large diffusion weighting, we measured the IMCL apparent diffusion coefficients (ADCs) in hindlimb muscle of rodents from normal feeding, 60-h fasting, streptozotocin-induced diabetic, and high-fat-diet-induced obese groups. RESULTS: IMCL ADCs decreased markedly with diffusion time, confirming the restricted diffusion of lipid molecules within IMCL droplets. IMCL droplet size, determined by transmission electron microscopy, was closely correlated with ADC. IMCL ADC was sensitive to metabolic alterations, decreasing in the 60-h fasting and diabetic groups while increasing in the obese group. These findings indicated that the IMCL droplet size decreased following 60-h fasting and in STZ-induced diabetes but increased in high-fat-diet-induced obesity. CONCLUSION: MR diffusion characterization of IMCL droplet size provides a unique means to examine the intracellular lipid dynamics and metabolic abnormalities in vivo.

Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI.

PURPOSE: Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. METHODS: Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. RESULTS: Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. CONCLUSIONS: High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury.

In vivo visuotopic brain mapping with manganese-enhanced MRI and resting-state functional connectivity MRI.

The rodents are an increasingly important model for understanding the mechanisms of development, plasticity, functional specialization and disease in the visual system. However, limited tools have been available for assessing the structural and functional connectivity of the visual brain network globally, in vivo and longitudinally. There are also ongoing debates on whether functional brain connectivity directly reflects structural brain connectivity. In this study, we explored the feasibility of manganese-enhanced MRI (MEMRI) via 3 different routes of Mn(2+) administration for visuotopic brain mapping and understanding of physiological transport in normal and visually deprived adult rats. In addition, resting-state functional connectivity MRI (RSfcMRI) was performed to evaluate the intrinsic functional network and structural-functional relationships in the corresponding anatomical visual brain connections traced by MEMRI. Upon intravitreal, subcortical, and intracortical Mn(2+) injection, different topographic and layer-specific Mn enhancement patterns could be revealed in the visual cortex and subcortical visual nuclei along retinal, callosal, cortico-subcortical, transsynaptic and intracortical horizontal connections. Loss of visual input upon monocular enucleation to adult rats appeared to reduce interhemispheric polysynaptic Mn(2+) transfer but not intra- or inter-hemispheric monosynaptic Mn(2+) transport after Mn(2+) injection into visual cortex. In normal adults, both structural and functional connectivity by MEMRI and RSfcMRI was stronger interhemispherically between bilateral primary/secondary visual cortex (V1/V2) transition zones (TZ) than between V1/V2 TZ and other cortical nuclei. Intrahemispherically, structural and functional connectivity was stronger between visual cortex and subcortical visual nuclei than between visual cortex and other subcortical nuclei. The current results demonstrated the sensitivity of MEMRI and RSfcMRI for assessing the neuroarchitecture, neurophysiology and structural-functional relationships of the visual brains in vivo. These may possess great potentials for effective monitoring and understanding of the basic anatomical and functional connections in the visual system during development, plasticity, disease, pharmacological interventions and genetic modifications in future studies.

Bilateral substantia nigra and pyramidal tract changes following experimental intracerebral hemorrhage: an MR diffusion tensor imaging study.

The amelioration of secondary neurological damage is among the most important therapeutic goals for patients with intracerebral hemorrhage (ICH). Secondary injury of the ipsilateral substantia nigra (SN) and pyramidal tract (PY) is common after cerebral stroke. Such injury has been characterized previously by anatomical or diffusion MRI, but not in a comprehensive manner, and the knowledge regarding the contralateral changes is relatively poor. This study examined longitudinally both contralateral and ipsilateral SN and PY changes following experimental ICH with diffusion tensor imaging (DTI) and histology. ICH was induced in 14 Sprague-Dawley rats by the infusion of collagenase into the right striatum. Four-shot, spin-echo, echo-planar DTI was performed at 7 T with a b value of 1000 s/mm(2) and 30 diffusion gradient directions at 3.5 h and days 1, 3, 7, 14, 42 and 120 after ICH. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ// ) and radial diffusivity (λ┴ ) were measured in SN and PY accordingly. Two to three rats were sacrificed at days 3, 7, 42 and 120 for histology. The contralateral SN showed an increase in λ// with perivascular enlargement during the first 3 days after ICH. The ipsilateral SN showed increases in FA, λ// , λ┴ and MD at day 1, dramatic decreases at day 3 with neuronal degeneration and neuropil vacuolation, and subsequent gradual normalization. The contralateral PY showed diffusivity decreases at day 1. The ipsilateral PY showed early decreases and then late increases in MD and λ┴, and continuously decreasing FA and λ// with progressive axonal loss and demyelination. In summary, DTI revealed early bilateral changes in SN and PY following ICH. The evolution of the ipsilateral parameters correlated with the histological findings. In the ipsilateral PY, λ// and λ┴ changes indicated evolving and complex pathological processes underlying the monotonic FA decrease. These results support the use of quantitative multiparametric DTI for the evaluation of SN and PY injuries in clinical and preclinical investigations of ICH.

Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model.

OBJECTIVES: Cyclic decapeptide CGLIIQKNEC (CLT1) has been demonstrated to target fibronectin-fibrin complexes in the extracellular matrix of different tumors and tissue lesions. Although liver fibrosis is characterized by an increased amount of extracellular matrix consisting of fibril-forming collagens and matrix glycoconjugates such as fibronectin, we aimed to investigate the feasibility of detecting and characterizing liver fibrosis using CLT1 peptide-targeted nanoglobular contrast agent (Gd-P) with dynamic contrast-enhanced magnetic resonance imaging in an experimental mouse model of liver fibrosis at 7 T. MATERIALS AND METHODS: Gd-P, control peptide KAREC conjugated nanoglobular contrast agent (Gd-CP), and control nontargeting nanoglobular contrast agent (Gd-C) were synthesized. Male adult C57BL/6N mice (22-25 g; N = 54) were prepared and were divided into fibrosis (n = 36) and normal (n = 18) groups. Liver fibrosis was induced in the fibrosis group through subcutaneous injection of 1:3 mixture of carbon tetrachloride (CCl(4)) in olive oil at a dose of 4 µL/g of body weight twice a week for 8 weeks. Dynamic contrast-enhanced MRI was performed in all animals. Dynamic contrast-enhanced magnetic resonance imaging was analyzed to yield postinjection ΔR(1)(t) maps for quantitative measurements. Histological analysis was also performed. RESULTS: Differential enhancements were observed and characterized between the normal and fibrotic livers using Gd-P at 0.03 mmol/kg, when compared with nontargeted controls (Gd-CP and Gd-C). For Gd-P injection, both the peak and steady-state ΔR(1) of the normal livers were significantly lower than those after 4 and 8 weeks of CCl(4) dosing. Liver fibrogenesis with increased amount of fibronectin in the extracellular space in insulted livers were confirmed by histological observations. CONCLUSIONS: These results indicated that dynamic contrast-enhanced magnetic resonance imaging with CLT1 peptide-targeted nanoglobular contrast agent can detect and stage liver fibrosis by probing the accumulation of fibronectin in fibrotic livers.

High fidelity tonotopic mapping using swept source functional magnetic resonance imaging.

Tonotopy, the topographic encoding of sound frequency, is the fundamental property of the auditory system. Invasive techniques lack the spatial coverage or frequency resolution to rigorously investigate tonotopy. Conventional auditory fMRI is corrupted by significant image distortion, sporadic acoustic noise and inadequate frequency resolution. We developed an efficient and high fidelity auditory fMRI method that integrates continuous frequency sweeping stimulus, distortion free MRI sequence with stable scanner noise and Fourier analysis. We demonstrated this swept source imaging (SSI) in the rat inferior colliculus and obtained tonotopic maps with ~2 kHz resolution and 40 kHz bandwidth. The results were vastly superior to those obtained by conventional fMRI mapping approach and in excellent agreement with invasive findings. We applied SSI to examine tonotopic injury following developmental noise exposure and observed that the tonotopic organization was significantly disrupted. With SSI, we also observed the subtle effects of sound pressure level on tonotopic maps, reflecting the complex neuronal responses associated with asymmetric tuning curves. This in vivo and noninvasive technique will greatly facilitate future investigation of tonotopic plasticity and disorders and auditory information processing. SSI can also be adapted to study topographic organization in other sensory systems such as retinotopy and somatotopy.