Browsing by Author "Liu, Chunlei"
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Item Open Access Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults.(Neuroimage, 2015-01-15) Li, Wei; Langkammer, Christian; Chou, Ying-Hui; Petrovic, Katja; Schmidt, Reinhold; Song, Allen W; Madden, David J; Ropele, Stefan; Liu, ChunleiIn the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility--a surrogate marker of brain iron--of these gray matter structures with behavioral measures of motor and cognitive abilities, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes.Item Open Access Cortical iron mediates age-related decline in fluid cognition.(Human brain mapping, 2022-02) Howard, Cortney M; Jain, Shivangi; Cook, Angela D; Packard, Lauren E; Mullin, Hollie A; Chen, Nan-Kuei; Liu, Chunlei; Song, Allen W; Madden, David JBrain iron dyshomeostasis disrupts various critical cellular functions, and age-related iron accumulation may contribute to deficient neurotransmission and cell death. While recent studies have linked excessive brain iron to cognitive function in the context of neurodegenerative disease, little is known regarding the role of brain iron accumulation in cognitive aging in healthy adults. Further, previous studies have focused primarily on deep gray matter regions, where the level of iron deposition is highest. However, recent evidence suggests that cortical iron may also contribute to cognitive deficit and neurodegenerative disease. Here, we used quantitative susceptibility mapping (QSM) to measure brain iron in 67 healthy participants 18-78 years of age. Speed-dependent (fluid) cognition was assessed from a battery of 12 psychometric and computer-based tests. From voxelwise QSM analyses, we found that QSM susceptibility values were negatively associated with fluid cognition in the right inferior temporal gyrus, bilateral putamen, posterior cingulate gyrus, motor, and premotor cortices. Mediation analysis indicated that susceptibility in the right inferior temporal gyrus was a significant mediator of the relation between age and fluid cognition, and similar effects were evident for the left inferior temporal gyrus at a lower statistical threshold. Additionally, age and right inferior temporal gyrus susceptibility interacted to predict fluid cognition, such that brain iron was negatively associated with a cognitive decline for adults over 45 years of age. These findings suggest that iron may have a mediating role in cognitive decline and may be an early biomarker of neurodegenerative disease.Item Open Access Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan.(Human Brain Mapping, 2014-06) Li, Wei; Wu, Bing; Batrachenko, Anastasia; Bancroft-Wu, Vivian; Morey, Rajendra A; Shashi, Vandana; Langkammer, Christian; De Bellis, Michael D; Ropele, Stefan; Song, Allen W; Liu, ChunleiAs indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing.Item Open Access Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans.(Human Brain Mapping, 2013-11) Morey, Rajendra A; Haswell, Courtney C; Selgrade, Elizabeth S; Massoglia, Dino; Liu, Chunlei; Weiner, Jonathan; Marx, Christine E; MIRECC Work Group; Cernak, Ibolja; McCarthy, GregoryMild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events.Item Open Access Higher Order Tensor Diffusion Imaging of Complex White Matter Fiber Tracts(2012) Murphy, Nicole EResolving multiple fiber orientations within one imaging voxel is critical for accurate quantification of tissue microstructure and faithful reconstruction of the complex neural fiber pathways. It is recognized that the diffusion process in brain tissues is generally non-Gaussian and recently there have been multiple methods developed specifically to account for this non-Gaussian property. Many of these efforts, however, have been largely focused on improving fiber tracking algorithms rather than providing a quantitative assessment of the deviation from Gaussian diffusion. Consequently, fast and quantitative assessment of this non-Gaussian property is critically needed. Developing a quantitative measurement of the non-Gaussian diffusion processes may provide powerful tools to assess changes in white matter that are due to axonal damage or degeneration. Generalized diffusion tensor imaging (GDTI) with the use of higher order tensors (HOT) provides one such method to identify, characterize and visualize underlying fiber structures. An optimal scan protocol, which estimates the fourth-order diffusion tensor, is needed in order to maximize the efficiency and speed of the data acquisition. This optimization was investigated for a phantom that models crossing white matter fibers and compared to in vivo scans. The minimum number of b-values, b-value magnitudes, and the minimum number of gradient directions sufficient to estimate fourth order diffusion tensors was identified.
Gold standards were established by acquiring images using five b-values and a large number of gradient directions for both the phantom and in vivo data sets. The fourth order diffusion tensors were then calculated for one, two, and three b-value subsets of the original five b-value data for both phantom and in vivo cases. For each subset, the tensors were converted to a two-dimensional 9×9 matrix and decomposed using eigenvalue decomposition. Three scalar metrics were developed to characterize the non-Gaussian diffusion. The mean of the eigenvalues represents the fourth-order deviation from a Gaussian diffusion, the fourth order FA provides a measure of the variance within the fourth order diffusion distribution, and the variance-to-mean ratio (VMR) characterizes the signal distribution across the eigenvalues.
The scalar metrics for each b-value subset was compared to the gold standard by way of a Root Mean Square Error (RMSE). The normalized RMSE was then plotted for each metric across all subsets and the b-value magnitude combination corresponding to the lowest error was identified. It was found that a single b-value is not sufficient for the scalar representation of the fourth order diffusion tensor. While a three b-value subset had the lowest error, it was shown that two b-values provided acceptable image quality and fourth order diffusion information.
Item Open Access In Vitro Calcium Imaging of Magnetogenetic Ion Channels TRPV1FeRIC and TRPV4FeRIC(2018) Gibbs, EricFerritin-based magnetogenetic ion channels are promising new tools for non-invasive manipulation of ion channel activity. The use of these channels in animals has been promising but in vitro experiments in cultured cells have been inconclusive. This report focuses on channels TRPV1FeRIC and TRPV4FeRIC whose channel activity is reportedly sensitive to an alternating magnetic field (AMF) at 175 MHz. In vitro work on these channels has previously been done, but those experiments did not have the necessary controls and had significant confounding factors. This dissertation addresses these problems and redesigns AMF calcium imaging experiments to more accurately measure an AMF response. After many experiments and careful analysis, it is concluded that 175 MHz AMF exposure does not change intracellular calcium concentration in HEK 293T cells expressing TRPV1FeRIC or TRPV4FeRIC.
Item Open Access MRI tools for assessment of microstructure and nephron function of the kidney.(Am J Physiol Renal Physiol, 2016-12-01) Xie, Luke; Bennett, Kevin M; Liu, Chunlei; Johnson, G Allan; Zhang, Jeff Lei; Lee, Vivian SMRI can provide excellent detail of renal structure and function. Recently, novel MR contrast mechanisms and imaging tools have been developed to evaluate microscopic kidney structures including the tubules and glomeruli. Quantitative MRI can assess local tubular function and is able to determine the concentrating mechanism of the kidney noninvasively in real time. Measuring single nephron function is now a near possibility. In parallel to advancing imaging techniques for kidney microstructure is a need to carefully understand the relationship between the local source of MRI contrast and the underlying physiological change. The development of these imaging markers can impact the accurate diagnosis and treatment of kidney disease. This study reviews the novel tools to examine kidney microstructure and local function and demonstrates the application of these methods in renal pathophysiology.Item Open Access Probing Tissue Microstructure Using Susceptibility Contrast Magnetic Resonance Imaging(2016) Dibb, RussellMagnetic resonance imaging is a research and clinical tool that has been applied in a wide variety of sciences. One area of magnetic resonance imaging that has exhibited terrific promise and growth in the past decade is magnetic susceptibility imaging. Imaging tissue susceptibility provides insight into the microstructural organization and chemical properties of biological tissues, but this image contrast is not well understood. The purpose of this work is to develop effective approaches to image, assess, and model the mechanisms that generate both isotropic and anisotropic magnetic susceptibility contrast in biological tissues, including myocardium and central nervous system white matter.
This document contains the first report of MRI-measured susceptibility anisotropy in myocardium. Intact mouse heart specimens were scanned using MRI at 9.4 T to ascertain both the magnetic susceptibility and myofiber orientation of the tissue. The susceptibility anisotropy of myocardium was observed and measured by relating the apparent tissue susceptibility as a function of the myofiber angle with respect to the applied magnetic field. A multi-filament model of myocardial tissue revealed that the diamagnetically anisotropy α-helix peptide bonds in myofilament proteins are capable of producing bulk susceptibility anisotropy on a scale measurable by MRI, and are potentially the chief sources of the experimentally observed anisotropy.
The growing use of paramagnetic contrast agents in magnetic susceptibility imaging motivated a series of investigations regarding the effect of these exogenous agents on susceptibility imaging in the brain, heart, and kidney. In each of these organs, gadolinium increases susceptibility contrast and anisotropy, though the enhancements depend on the tissue type, compartmentalization of contrast agent, and complex multi-pool relaxation. In the brain, the introduction of paramagnetic contrast agents actually makes white matter tissue regions appear more diamagnetic relative to the reference susceptibility. Gadolinium-enhanced MRI yields tensor-valued susceptibility images with eigenvectors that more accurately reflect the underlying tissue orientation.
Despite the boost gadolinium provides, tensor-valued susceptibility image reconstruction is prone to image artifacts. A novel algorithm was developed to mitigate these artifacts by incorporating orientation-dependent tissue relaxation information into susceptibility tensor estimation. The technique was verified using a numerical phantom simulation, and improves susceptibility-based tractography in the brain, kidney, and heart. This work represents the first successful application of susceptibility-based tractography to a whole, intact heart.
The knowledge and tools developed throughout the course of this research were then applied to studying mouse models of Alzheimer’s disease in vivo, and studying hypertrophic human myocardium specimens ex vivo. Though a preliminary study using contrast-enhanced quantitative susceptibility mapping has revealed diamagnetic amyloid plaques associated with Alzheimer’s disease in the mouse brain ex vivo, non-contrast susceptibility imaging was unable to precisely identify these plaques in vivo. Susceptibility tensor imaging of human myocardium specimens at 9.4 T shows that susceptibility anisotropy is larger and mean susceptibility is more diamagnetic in hypertrophic tissue than in normal tissue. These findings support the hypothesis that myofilament proteins are a source of susceptibility contrast and anisotropy in myocardium. This collection of preclinical studies provides new tools and context for analyzing tissue structure, chemistry, and health in a variety of organs throughout the body.
Item Open Access Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.(Nature, 2013-05) Benner, Eric J; Luciano, Dominic; Jo, Rebecca; Abdi, Khadar; Paez-Gonzalez, Patricia; Sheng, Huaxin; Warner, David S; Liu, Chunlei; Eroglu, Cagla; Kuo, Chay TPostnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx)(+) neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that it is these SVZ-generated Thbs4(hi) astrocytes, and not Dcx(+) neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4(KO/KO)) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4(KO/KO) mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.Item Open Access Quantitative Magnetic Susceptibility of the Developing Mouse Brain(2012) Argyridis, IoannisCerebral development involves a complex cascade of events which are difficult
to visualize in vivo. In this study we combine information from Diffusion Tensor
Imaging (DTI) and Quantitative Susceptibility Mapping (QSM) on developing mouse
brains at five stages, for three central white matter (WM) regions. QSM can be calculated
using frequency shift Gradient Echo MR images acquired at high field. Extracted mean
values from small white matter regions of QSM brain maps depend on the orientation of
the neuronal fibers of each voxel to the main magnetic field B0. Using fiber tracking
information from DTI a correlation of the myelin content of regions of interest (ROI) to
the orientation of those fibers to B0 can be made. Plots of the myelin anisotropy, as it
increases with age, were generated with this method, suggesting that the neuronal axon
is paramagnetic while the myelin surrounding the axon is diamagnetic. In addition the
fractional anisotropy (FA) and the mean Apparent Diffusion Coefficient (ADC) of the
same ROI were plotted against age. Histological exams were also performed to evaluate
myelin and iron content. It is confirmed that the main source of magnetic susceptibility in WM
is the myelin content. The interpretation of all this brain data will provide valuable
information on the architecture of the brain during development and a more accurate
diagnosis in the case of a myelin degenerative disease.
Item Open Access Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.(Science signaling, 2017-10) Hutson, Mary R; Keyte, Anna L; Hernández-Morales, Miriam; Gibbs, Eric; Kupchinsky, Zachary A; Argyridis, Ioannis; Erwin, Kyle N; Pegram, Kelly; Kneifel, Margaret; Rosenberg, Paul B; Matak, Pavle; Xie, Luke; Grandl, Jörg; Davis, Erica E; Katsanis, Nicholas; Liu, Chunlei; Benner, Eric JBirth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.