In vivo detection of individual glomeruli in the rodent olfactory bulb using manganese enhanced MRI

MRI contrast based on relaxation times, proton density, or signal phase have been applied to delineate neural structures in the brain. However, neural units such as cortical layers and columns have been difficult to identify using these methods. Manganese ion delivered either systemically or injected directly has been shown to accumulate specifically within cellular areas of the brain enabling the differentiation of layers within the hippocampus, cortex, cerebellum, and olfactory bulb in vivo. Here we show the ability to detect individual olfactory glomeruli using manganese enhanced MRI (MEMRI). Glomeruli are anatomically distinct structures (～150 μm in diameter) on the surface of the olfactory bulb that represent the first processing units for olfactory sensory information. Following systemic delivery of MnCl₂ we used 3D-MRI with 50 μm isotropic resolution to detect discrete spots of increased signal intensity between 100 and 200 μm in diameter in the glomerular layer of the rat olfactory bulb. Inflow effects of arterial blood and susceptibility effects of venous blood were suppressed and were evaluated by comparing the location of vessels in the bulb to areas of manganese enhancement using iron oxide to increase vessel contrast. These potential vascular effects did not explain the contrast detected. Nissl staining of individual glomeruli were also compared to MEMRI images from the same animals clearly demonstrating that many of the manganese enhanced regions corresponded to individual olfactory glomeruli. Thus, MEMRI can be used as a non-invasive means to detect olfactory glomeruli for longitudinal studies looking at neural plasticity during olfactory development or possible degeneration associated with disease.     

Uptake and retention of manganese contrast agents for PET and MRI in the rodent brain

Manganese‐enhanced magnetic resonance imaging (MRI) is an established neuroimaging method for signal enhancement, tract tracing, and functional studies in rodents. Along with the increasing availability of combined positron emission tomography (PET) and MRI scanners, the recent development of the positron‐emitting isotope ⁵²Mn has prompted interest in the use of Mn²⁺ as a dual‐modality contrast agent. In this work, we characterized and compared the uptake of systemically delivered Mn²⁺ and radioactive ⁵²Mn²⁺ in the rat brain for MRI and PET, respectively. Additionally, we examined the biodistribution of two formulations of ⁵²Mn²⁺ in the rat. In MRI, maximum uptake was observed one day following delivery of the highest MnCl₂ dose tested (60 mg/kg), with some brain regions showing delayed maximum enhancement 2–4 days following delivery. In PET, we observed low brain uptake after systemic delivery, with a maximum of approximately 0.2% ID/g. We also studied the effect of final formulation vehicle (saline compared with MnCl₂) on ⁵²Mn²⁺ organ biodistribution and brain uptake. We observed that the addition of bulk Mn²⁺ carrier to ⁵²Mn²⁺ in solution resulted in significantly reduced ⁵²Mn²⁺ uptake in the majority of organs, including the brain. These results lay the groundwork for further development of ⁵²Mn PET or dual Mn‐enhanced PET–MR neuroimaging in rodents, and indicate several interesting potential applications of ⁵²Mn PET in other organs and systems. Copyright © 2016 John Wiley & Sons, Ltd.     

In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI

Visualizing brain anatomy in vivo could provide insight into normal and pathophysiology. Here it is demonstrated that neuroarchitecture can be detected in the rodent brain using MRI after systemic MnCl2. Administration of MnCl2 leads to rapid T1 enhancement in the choroid plexus and circumventricular organs, which spreads to the CSF space in ventricles and periventricular tissue. After 1 day, there was MRI enhancement throughout the brain with high intensity in the pituitary, olfactory bulb, cortex, basal forebrain, hippocampus, basal ganglia, hypothalamus, amygdala, and cerebellum. Contrast obtained enabled visualization of specific features of neuroarchitecture. The arrowhead structure of the dentate gyrus as well as the CA1-CA3 region of the hippocampus and layers in cortex, cerebellum, as well as the olfactory bulb could be readily observed. Preliminary assignments of olfactory bulb layers, cortical layers in frontal and somatosensory cortex, and cerebellum were made. Systemic MnCl2 leads to MRI visualization of neuroarchitecture nondestructively.     

Analysis of laminar activity in normal and injured rat spinal cord by manganese enhanced MRI

The present study provides an account of a sensitive and rapid experimental approach for MRI visualization and analysis of spinal cord (SC) laminar activity in normal and injured animals. This approach is based upon neuronal activity-dependant manganese (Mn) uptake after focal SC injection of MnCl(2), and subsequent ex-vivo magnetic resonance imaging (MRI) of activated SC pathways. The method was designed as an alternative to time-intensive histochemical and behavioral approaches typically used for analysis of spinal cord injury (SCI) and our results provide both anatomical and functional insights. We show that ex vivo imaging can determine layer-specific activity over an extended region of the rat SC. In addition, we demonstrate that the Mn concentration profile along the SC axis accurately reflects the type of SC injury. The approach is flexible since MRI analysis can be done immediately after animal sacrifice, or alternatively several days later, without a loss of sensitivity. Moreover, the integrity and functional state of SC circuitry can be analyzed in less than 1 h whereas several days and weeks are necessary to perform classical histochemical and behavioral analysis. Thus our method can be used for precise assessment of the extent of dysfunction or change in SC disorders and may facilitate the screening of molecules with therapeutic potential after SC injury.     

Functional tracing of medial nociceptive pathways using activity-dependent manganese-enhanced MRI

Manganese ion (Mn²⁺) was used as a paramagnetic contrast agent in T1-weighted magnetic resonance imaging (MRI) images. They enter neural cells though voltage-gated calcium channels and are activity-dependently transported along axons and across synapses. The aim of the present study was to investigate the nociceptive medial thalamus projection in rats by activity-dependent manganese-enhanced magnetic resonance imaging (MEMRI). Rats under urethane and α-chloralose anesthesia were microinjected with manganese chloride (MnCl₂, 120 mmol/L, iontophoretically with a 5-μA current for 15 min) into the right medial thalamus. Innocuous (at a 50-μA intensity for 0.2 ms) or noxious (at a 5-mA intensity for 2 ms) electrical stimuli were applied through a pair of needles in the left forepaw pads once every 6 s for 5 h. Enhanced transport of Mn²⁺ were found in the anterior cingulate cortex, midcingulate cortex, retrosplenial cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala in the noxious-stimulated group. Enhancements in the anterior cingulate cortex, midcingulate cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala, but not the retrosplenial cortex, were attenuated by an intraperitoneal injection of morphine (5 mg/kg and 1 mg/kg/h, intraperitoneal). These results indicate that a combination of MEMRI with activity-induced manganese-dependent contrast is useful for delineating functional connections in the pain pathway.     

Attention to action: specific modulation of corticocortical interactions in humans

The prefrontal cortex may exert cognitive control by a general mechanism of attentional selection of neuronal representations. We used functional magnetic resonance imaging to test this hypothesis in the motor system. Normal volunteers were scanned during performance of a simple motor task, with their attention either directed towards their actions, or diverted towards a visual search task, or neither. Attention to action increased activity in prefrontal, premotor and parietal cortex, compared with unattended performance of the same movements. Analysis of cortical activity by structural equation modelling of regional fMRI time series was used to measure effective connectivity among prefrontal, premotor and parietal cortices. Attention to action enhanced effective connectivity between dorsal prefrontal cortex and premotor cortex, whereas non-motor attention diminished it. These effects were not attributable to common inputs from parietal cortex to the prefrontal and premotor cortex. The results suggest a supra-modal role for the dorsal prefrontal cortex in attentional selection, operating within the motor system as well as sensory and mnemonic domains.     

In vivo mapping of functional connectivity in neurotransmitter systems using pharmacological MRI

Pharmacological MRI (phMRI) methods map the hemodynamic response to drug challenge as a surrogate for changes in neuronal activity. However, the central effects of drugs can be complex and include activity at the primary site of action, downstream effects in other brain regions and direct effects on vasculature and neurovascular coupling. Univariate analysis, normally applied to phMRI data, does not discriminate between these effects, and can result in anatomically non-specific activation patterns. We analysed inter-subject correlations in the amplitude of the slow phMRI response to map functionally connected brain regions recruited in response to pharmacological challenge. Application of d-amphetamine and fluoxetine revealed well-defined functional structure underlying the widespread signal changes detected via standard methods. Correlated responses were found to delineate key neurotransmitter pathways selectively targeted by these drugs, corroborating a tight correspondence between the phMRI response and changes in neurotransmitter systems specific to the pharmacological action. In vivo mapping of correlated responses in this way greatly extends the range of information available from phMRI studies and provides a new window into the function of neurotransmitter systems in the active state. This approach may provide new important insights regarding the central systems underlying pharmacological action.     

Defining functional areas in individual human brains using resting functional connectivity MRI

The cerebral cortex is anatomically organized at many physical scales starting at the level of single neurons and extending up to functional systems. Current functional magnetic resonance imaging (fMRI) studies often focus at the level of areas, networks, and systems. Except in restricted domains, (e.g., topographically-organized sensory regions), it is difficult to determine area boundaries in the human brain using fMRI. The ability to delineate functional areas non-invasively would enhance the quality of many experimental analyses allowing more accurate across-subject comparisons of independently identified functional areas. Correlations in spontaneous BOLD activity, often referred to as resting state functional connectivity (rs-fcMRI), are especially promising as a way to accurately localize differences in patterns of activity across large expanses of cortex. In the current report, we applied a novel set of image analysis tools to explore the utility of rs-fcMRI for defining wide-ranging functional area boundaries. We find that rs-fcMRI patterns show sharp transitions in correlation patterns and that these putative areal boundaries can be reliably detected in individual subjects as well as in group data. Additionally, combining surface-based analysis techniques with image processing algorithms allows automated mapping of putative areal boundaries across large expanses of cortex without the need for prior information about a region's function or topography. Our approach reliably produces maps of bounded regions appropriate in size and number for putative functional areas. These findings will hopefully stimulate further methodological refinements and validations.     

Deficits in axonal transport in hippocampal-based circuitry and the visual pathway in APP knock-out animals witnessed by manganese enhanced MRI

Mounting evidence implicates axonal transport defects, typified by the presence of axonal varicosities with aberrant accumulations of cargo, as an early event in Alzheimer's disease (AD) pathogenesis. Work identifying amyloid precursor protein (APP) as a vesicular motor receptor for anterograde axonal transport further implicates axonal transport in AD. Manganese-enhanced MRI (MEMRI) detects axonal transport dynamics in preclinical studies. Here we pursue an understanding of the role of APP in axonal transport in the central nervous system by applying MEMRI to hippocampal circuitry and to the visual pathway in living mice homozygous for either wild type or a deletion in the APP gene (n=12 for each genotype). Following intra-ocular or stereotaxic hippocampal injection, we performed time-lapse MRI to detect Mn(2+) transport. Three dimensional whole brain datasets were compared on a voxel-wise basis using within-group pair-wise analysis. Quantification of transport to structures connected to injection sites via axonal fiber tracts was also performed. Histology confirmed consistent placement of hippocampal injections and no observable difference in glial-response to the injections. APP-/- mice had significantly reduced transport from the hippocampus to the septal nuclei and amygdala after 7h and reduced transport to the contralateral hippocampus after 25 h; axonal transport deficits in the APP-/- animals were also identified in the visual pathway. These data support a system-wide role for APP in axonal transport within the central nervous system and demonstrate the power of MEMRI for assessing neuronal circuitry involved in memory and learning.     

The effects of glutamate receptor agonists and antagonists on mouse hypothalamic and hippocampal neuronal activity shown through manganese enhanced MRI

Manganese enhanced MRI (MEMRI) is an imaging paradigm that can be used to assess neuronal activity in vivo. Here we investigate, through the use of MEMRI, the influence of receptor dynamics on neuronal activity in the hypothalamus and hippocampus focusing on the glutamate receptor signalling system. We demonstrate that intraperitoneal (i.p.) administration of monosodium glutamate (MSG) and the ionotropic glutamate receptor (iGluR) agonists NMDA and AMPA resulted in significantly increased signal intensity (SI) in the arcuate nucleus (ARC), the suprachiasmatic nucleus (SCN) and the CA3 region of the hippocampus of mice consistent with increased neuronal activity. Administration of the NMDA receptor antagonist MK-801 resulted in significantly decreased SI in the paraventricular nucleus (PVN) consistent with decreased neuronal activity. Co-administration of MSG and the AMPA receptor antagonist NBQX attenuated the increase in SI observed in the ARC from MSG alone, suggesting MEMRI may be applicable to the study of receptor dynamics in vivo. We also observed that administration of the various iGluR agonists and antagonists modulated SI in the lateral ventricle and that high dose MSG (300 mg) caused a hitherto unseen enhancement in SI in the entire cortical/subarachnoid region. In conclusion, MEMRI reveals changes in neuronal activity in response to iGluR agonists and antagonists in the CNS in vivo as well as revealing multifaceted effects beyond those attributable to neuronal activity alone.     

MRI动态增强在甲状腺疾病诊断中的应用

目的 用MR动态增强检查技术分析甲状腺占位性病变动态增强特点,探讨良、恶性甲状腺病变的增强模式.材料与方法 搜集手术病理证实的甲状腺占位性病变42例(男10例,女32例),其中良性病变28例,恶性肿瘤14例.术前均行MRI常规和动态增强检查,获得时间-信号强度曲线(TIC),并计算最大强化率(ERmax)及最大上升斜率(Slopemax)等参数.对TIC的Slopemax值及ERmax值进行中位数检验(两独立样本的位置检验).结果 TIC的Ⅰ型(快速上升型)曲线共21例,均为甲状腺良性病变,Ⅱ型(上升平台型)曲线9例,7例良性病变,2例滤泡样甲状腺癌,Ⅲ型(延迟上升型)曲线12例,均为甲状腺恶     

DiI的特性及在周围神经示踪中的应用

目的摸索DiI在周围神经示踪中的应用技巧，探讨其物理和生物学特性。方法应用不同示踪、操作方法，行周围神经干双向DiI示踪，测量其在神经干中的扩散速度，观察评价示踪效果。结果用DiI乙醇溶液示踪、冰冻切片、低光强下直接观察效果较好；在神经干内顺行、逆行扩散速度相同，不同时间组扩散速度有差异，DiI在神经干内的扩散具有轴突特异性。结论（1）DiI在周围神经示踪中的应用方法不同于在中枢神经；（2）DiI是一种良好的荧光类双向神经示踪剂，具有轴突特异性，可以用于活体神经束路的示踪研究。     

脊柱结核磁共振成像增强扫描的意义

目的通过分析脊柱结核的磁共振成像(magnetic resonance imaging,MRI)影像表现,提高对脊柱结核的诊断、认识。材料与方法回顾性分析经活检和手术病理检查证实的57例脊柱结核患者的MRI影像资料,分析脊柱结核MRI平扫及增强扫描影像表现。结果 57例患者中颈椎结核5例、胸椎结核12例、腰椎结核24例,颈椎合并胸椎3例,胸椎合并腰椎8例,腰椎合并骶椎5例。单椎体受累2例,相邻2个椎体受累41例,3个及3个以上椎体受累14例。43例椎间隙狭窄或消失,40例脓肿形成。增强扫描41例病灶区域明显强化,16例弱强化或无强化。57例患者均接受1~3月不等强化多联抗结核化疗治疗。15例患者术前多次行MR增强扫描检查,12例患者影像学表现不同程度好转,3例无明显变化。结论 MRI增强扫描对早期诊断脊柱结核及指导临床治疗有着重要的应用价值。     

The corpus callosum in schizophrenia-volume and connectivity changes affect specific regions

The corpus callosum (CC) is of great interest for pathophysiological models of schizophrenia. Volume and structural integrity of the CC have been examined by volumetric and diffusion tensor imaging (DTI) studies, but results were not consistent across methods or studies. A possible explanation may be varying methodologies and accuracy of measurements based on a single slice or small regions of interest. In addition, none of the studies examined volume and diffusion values in the same group of patients, and thus the relationship between these anatomical measures is not clear. We used an automatic algorithm to segment seven midline slices of the CC from DTI images. We compared volume and the DTI measures fractional anisotropy (FA) and mean diffusivity (MD) in the CC and its subdivisions in the schizophrenia patients and matched controls. Patients had decreased volume, decreased FA and increased MD of the whole CC. The important novel finding is, however, that not all regions were equally affected by anatomical changes. The results emphasize the importance of using different methods in evaluation of white matter (WM) in schizophrenia to avoid false negative findings. In addition, the measures were highly correlated with each other, implying a common pathological process influencing FA, MD and volume of the CC. Although we cannot rule out other mechanisms affecting volume, FA and MD, converging evidence from cytoarchitectonic and genetic studies suggests that WM changes observed in schizophrenia may involve disintegration of healthy, functional axons and strengthening of aberrant connections resulting in increased severity of clinical symptoms.     

Topographically specific functional connectivity between visual field maps in the human brain

Neural activity in mammalian brains exhibits large spontaneous fluctuations whose structure reveals the intrinsic functional connectivity of the brain on many spatial and temporal scales. Between remote brain regions, spontaneous activity is organized into large-scale functional networks. To date, it has remained unclear whether the intrinsic functional connectivity between brain regions scales down to the fine detail of anatomical connections, for example the fine-grained topographic connectivity structure in visual cortex. Here, we show that fMRI signal fluctuations reveal a detailed retinotopically organized functional connectivity structure between the visual field maps of remote areas of the human visual cortex. The structured coherent fluctuations were even preserved in complete darkness when all visual input was removed. While the topographic connectivity structure was clearly visible in within hemisphere connections, the between hemisphere connectivity structure differs for representations along the vertical and horizontal meridian respectively. These results suggest a tight link between spontaneous neural activity and the fine-grained topographic connectivity pattern of the human brain. Thus, intrinsic functional connectivity reflects the detailed connectivity structure of the cortex at a fine spatial scale. It might thus be a valuable tool to complement anatomical studies of the human connectome, which is one of the keys to understand the functioning of the human brain.     

Functional connectivity MRI in infants: exploration of the functional organization of the developing brain

Advanced neuroimaging techniques have been increasingly applied to the study of preterm and term infants in an effort to further define the functional cerebral architecture of the developing brain. Despite improved understanding of the complex relationship between structure and function obtained through these investigations, significant questions remain regarding the nature, location, and timing of the maturational changes which occur during early development. Functional connectivity magnetic resonance imaging (fcMRI) utilizes spontaneous, low frequency (< 0.1 Hz), coherent fluctuations in blood oxygen level dependent (BOLD) signal to identify networks of functional cerebral connections. Due to the intrinsic characteristics of its image acquisition and analysis, fcMRI offers a novel neuroimaging approach well suited to investigation of infants. Recently, this methodology has been successfully applied to examine neonatal populations, defining normative patterns of large-scale neural network development in the maturing brain. The resting-state networks (RSNs) identified in these studies reflect the evolving cerebral structural architecture, presumably driven by varied genetic and environmental influences. Principal features of these investigations and their role in characterization of the tenets of neural network development during this critical developmental period are highlighted in this review. Despite these successes, optimal methods for fcMRI data acquisition and analysis for this population have not yet been defined. Further, appropriate schemes for interpretation and translation of fcMRI results remain unknown, a matter of increasing importance as functional neuroimaging findings are progressively applied in the clinical arena. Notwithstanding these concerns, fcMRI provides insight into the earliest forms of cerebral connectivity and therefore holds great promise for future neurodevelopmental investigations.     

Sex differences in the development of neuroanatomical functional connectivity underlying intelligence found using Bayesian connectivity analysis

A Bayesian method for functional connectivity analysis was adapted to investigate between-group differences. This method was applied in a large cohort of almost 300 children to investigate differences in boys and girls in the relationship between intelligence and functional connectivity for the task of narrative comprehension. For boys, a greater association was shown between intelligence and the functional connectivity linking Broca's area to auditory processing areas, including Wernicke's areas and the right posterior superior temporal gyrus. For girls, a greater association was shown between intelligence and the functional connectivity linking the left posterior superior temporal gyrus to Wernicke's areas bilaterally. A developmental effect was also seen, with girls displaying a positive correlation with age in the association between intelligence and the functional connectivity linking the right posterior superior temporal gyrus to Wernicke's areas bilaterally. Our results demonstrate a sexual dimorphism in the relationship of functional connectivity to intelligence in children and an increasing reliance on inter-hemispheric connectivity in girls with age.     

Gd-BOPTA增强MRI评价肝功能储备

目的 探索钆贝葡胺（Gd-BOPTA）增强MRI评价肝功能储备的价值。方法 选择于我院接受Gd-BOPTA增强MR检查的患者143例,其中纳入68例。测量快速三维扰相梯度回波序列（LAVA-Flex）肝胆期肝实质各叶和全肝SNR强化率和CNR强化率。依据Child-Turcotte-Pugh（CTP）分级分为A级和B级,依据integrated MELD（iMELD）评分分为iMELD≤30和>30。比较组间SNR强化率与CNR强化率差异、分析强化率与肝功能评分之间的关系。结果 肝脏各叶及全肝SNR强化率、CNR强化率差异均无统计学意义（P均>0.05）。CTP分级A级患者全肝SNR和CNR强化率显著高于B级患者（P<0.05）。iMELD≤30患者全肝SNR和CNR强化率显著高于>30患者（P<0.05）。SNR强化率、CNR强化率与iMELD分值均呈负相关（r=-0.29、-0.32,P=0.02、0.01）。结论 肝细胞对Gd-BOPTA摄取量随着肝功能损害程度增加而下降,通过测量Gd-BOPTA增强MRI肝胆期分叶或全肝实质强化率,可以在一定程度上反映肝功能储备情况。