Kai Zhong

The molecular basis for gray and white matter contrast in phase imaging

Direct magnetic resonance phase images acquired at high field have been shown to yield superior gray and white matter contrast up to 10-fold higher compared to conventional magnitude images. However, the underlying contrast mechanism is not yet understood. This study demonstrates that the water resonance frequency is directly shifted by water-macromolecule exchange processes (0.040 ppm/mM for bovine serum albumin) and might be a major source of contribution to in vivo phase image contrast. Therefore, magnetic resonance phase imaging based on the proposed contrast mechanism could potentially be applied for in vivo studies of pathologies on a macromolecular level.

Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction

BACKGROUND Abnormalities in the white matter of the brain may occur in individuals with schizophrenia as well as with normal aging. Therefore, elderly schizophrenic patients may suffer further cognitive decline as they age. This study determined whether elderly schizophrenia participants, especially those with declined cognitive function (Clinical Dementia Rating score > 1), show white matter metabolite abnormalities on proton magnetic resonance spectroscopy and whether there are group differences in age-dependent changes in these brain metabolites. METHOD Twenty-three elderly schizophrenia and twenty-two comparison participants fulfilling study criteria were enrolled. Localized, short echo-time (1)H MRS at 4 Tesla was used to assess neurometabolite concentrations in several white matter regions. RESULTS Compared with healthy subjects, schizophrenia participants had lower N-acetyl compounds (-12.6%, p = .0008), lower myo-inositol (-16.4%, p = .026), and higher glutamate + glutamine (+28.7%, p = .0016) concentrations across brain regions. Schizophrenia participants with Clinical Dementia Rating >/= 1 showed the lowest NA in the frontal and temporal regions compared with control subjects. Interactions between age and schizophrenia status on total creatine and choline-containing compounds were observed; only schizophrenia participants showed age-related decreases of these metabolites in the right frontal region. CONCLUSIONS Decreased NA in these white matter brain regions likely reflects reduced neuronal content associated with decreased synapses and neuronal cell volumes. The elevated glutamate + glutamine, if reflecting elevated glutamate, could result from excess neuronal glutamate release or glial dysfunction in glutamate reuptake. The decreased myo-inositol in participants with schizophrenia suggests decreased glial content or dysfunctional glia, which might result from glutamate-mediated toxicity.

MR-Encephalography: Fast multi-channel monitoring of brain physiology with magnetic resonance

A new approach to measure activation-related changes in the brain by magnetic resonance is described offering high temporal resolution of 10-100 measurements per second. This is achieved by simultaneous multi-channel reception where the spatial resolution during continuous observation is determined by the sensitive volume of each coil alone without any additional spatial encoding gradients. Experimental results demonstrate the very high sensitivity of this approach, which allows to directly measure and monitor the stimulus-dependent hemodynamic response as well as ECG- and breathing-related signal fluctuations. One-dimensional spatial encoding either parallel or orthogonal to the cortex demonstrates that vascular signals can be identified by the pronounced signal variation at the ECG-frequency. Noise analysis at different frequencies reveals regional signal fluctuations in the frequency range between 2 and 10 Hz. Furthermore, initial results show that frequency changes in the order of <0.03 Hz corresponding to <1 nano Tesla can be detected. In addition to its potential use in neuroscientific studies, this new method opens a wide range of applications for fast physiological monitoring and can be easily combined with conventional high-resolution imaging.

Convergence behavior of iterative SENSE reconstruction with non-Cartesian trajectories

In non‐Cartesian SENSE reconstruction based on the conjugate gradient (CG) iteration method, the iteration very often exhibits a “semi‐convergence” behavior, which can be characterized as initial convergence toward the exact solution and later divergence. This phenomenon causes difficulties in automatic implementation of this reconstruction strategy. In this study, the convergence behavior of the iterative SENSE reconstruction is analyzed based on the mathematical principle of the CG method. It is revealed that the semi‐convergence behavior is caused by the ill‐conditioning of the underlying generalized encoding matrix (GEM) and the intrinsic regularization effect of CG iteration. From the perspective of regularization, each iteration vector is a regularized solution and the number of iterations plays the role of the regularization parameter. Therefore, the iteration count controls the compromise between the SNR and the residual aliasing artifact. Based on this theory, suggestions with respect to the stopping rule for well‐behaved reconstructions are provided. Simulated radial imaging and in vivo spiral imaging are performed to demonstrate the theoretical analysis on the semi‐convergence phenomenon and the stopping criterion. The dependence of convergence behavior on the undersampling rate and the noise level in samples is also qualitatively investigated. Magn Reson Med, 2005.

Systematic Regional Variations of GABA, Glutamine, and Glutamate Concentrations Follow Receptor Fingerprints of Human Cingulate Cortex

Magnetic resonance spectroscopy (MRS) of glutamatergic or GABAergic measures in anterior cingulate cortex (ACC) was found altered in psychiatric disorders and predictive of interindividual variations of functional responses in healthy populations. Several ACC subregions have been parcellated into receptor-architectonically different portions with heterogeneous fingerprints for excitatory and inhibitory receptors. Similarly, these subregions overlap with functionally distinct regions showing opposed signal changes toward stimulation or resting conditions. We therefore investigated whether receptor-architectonical and functional segregation of the cingulate cortex in humans was also reflected in its local concentrations of glutamate (Glu), glutamine (Gln), and GABA. To accomplish a multiregion estimation of all three metabolites in one robust and reliable session, we used an optimized 7T-stimulated echo-acquisition mode method with variable-rate selective excitation pulses. Our results demonstrated that, ensuring high data retest reliability, four cingulate subregions discerning e.g., pregenual ACC (pgACC) from anterior mid-cingulate cortex showed different metabolite concentrations and ratios reflective of regionally specific inhibition/excitation balance. These findings could be controlled for potential influences of local gray matter variations or MRS voxel-placement deviations. Pregenual ACC was found to have significantly higher GABA and Glu concentrations than other regions. This pattern was not paralleled by Gln concentrations, which for both absolute and relative values showed a rostrocaudal gradient with highest values in pgACC. Increased excitatory Glu and inhibitory GABA in pgACC were shown to follow a regional segregation agreeing with recently shown receptor-architectonic GABAB receptor distribution in ACC, whereas Gln distribution followed a pattern of AMPA receptors.

Systematic investigation of balanced steady-state free precession for functional MRI in the human visual cortex at 3 Tesla.

Previous studies have applied balanced steady‐state free precession (bSSFP) to functional brain imaging. Methods that exploit the strong frequency dependence of the MR signal in the bSSFP transition band are strongly affected by field inhomogeneity and frequency drifts. Recent bSSFP studies using “on‐resonance” (in the bSSFP passband) acquisition claimed that higher sensitivity was achieved compared to traditional fMRI methods. However, the contrast mechanism that generates activation‐related signal changes in bSSFP imaging is not yet fully understood. We performed a systematic study of on‐resonance bSSFP signal behavior using a multiecho balanced SSFP sequence with different TRs at 3 Tesla. We conclude that intravoxel dephasing, or the off‐resonance averaged steady state, dominates the bSSFP signal decay and determines the bSSFP fMRI contrast. Experimental findings were confirmed by simulations based on existing theories for signal formation around blood vessels in inhomogeneous tissues. The activation‐induced signal change in on‐resonance bSSFP increases with TE, and the TE dependence of the contrast‐to‐noise ratio (CNR) in bSSFP is similar to that in gradient echo‐planar imaging (GE‐EPI). However, GE‐EPI has a significantly higher CNR efficiency. Magn Reson Med 57:67–73, 2007.

Phase Contrast Imaging in Neonates

Magnetic resonance phase images can yield superior gray and white matter contrast compared to conventional magnitude images. However, the underlying contrast mechanisms are not yet fully understood. Previous studies have been limited to high field acquisitions in adult volunteers and patients. In this study, phase imaging in the neonatal brain is demonstrated for the first time. Compared to adults, phase differences between gray and white matter are significantly reduced but not inverted in neonates with little myelination and iron deposits in their brains. The remaining phase difference between the neonatal and adult brains may be due to a different macromolecule concentration in the unmyelinated brain of the neonates and thus a different frequency due to water macromolecule exchange. Additionally, the susceptibility contrast from brain myelination can be separately studied in neonates during brain development. Therefore, magnetic resonance phase imaging is suggested as a novel tool to study neonatal brain development and pathologies in neonates.

Using magnetic resonance imaging to study enzymatic hydrogelation.

Herein, we report, for the first time, the use of MRI methods to study enzymatic hydrogelation. Supramolecular hydrogels have been exploited as biomaterials for many applications. However, behaviors of the water molecules encapsulated in hydrogels have not been fully understood. In this work, we designed a precursor 1 which could self-assemble into nanofibers and form hydrogel I (gel I) upon the catalysis of phosphatase. The differences of mechanic property, pore size, water diffusion rate, and magnetic resonance relaxation times T1 and T2 of gel I containing different concentrations of 1 were systematically studied and analyzed. T1, T2, and diffusion-weighted (1)H MR images from gel I phantoms were obtained at 9.4 T. Analyses of the MRI data uncovered how the density of the nanofiber networks affects the relaxation behaviors of the water protons encapsulated in such hydrogels. Rheological analyses and cryo-TEM observations showed increased gel elasticities with increased concentrations of 1 while the pore sizes of gel I decreased. This also resulted in an increase in the proton relaxation rate (i.e., shortened T1, T2, and apparent diffusion coefficient (ADC)) for the water encapsulated in the hydrogel. With MRI, our study provides a new in vitro method to potentially mimic and study in vivo diseases that involve fibrous aggregates.

Accurate quantification of water–macromolecule exchange induced frequency shift: Effects of reference substance

Water–macromolecule exchange induces a bulk water frequency shift contributing to the contrast in phase imaging. For separating the effects of the water–macromolecule exchange and the macromolecule susceptibility, appropriate internal or external references are needed. In this study, two internal reference compounds, 2,2,3,3‐tetradeuterio‐3‐trimethylsilyl‐propionate (TMSP) and 1,4‐dioxane, were used to study the macromolecule‐dependent water frequency shift in a bovine serum albumin (BSA)–water system in detail. For TMSP, the water–macromolecule exchange shift depended on both the BSA and the reference concentration and stabilized to a value of 0.025 ppm/mM (298 K, TMSP concentrations > 30 mM). For dioxane, the dependency of the water–macromolecule exchange shift on the BSA concentration is independent of dioxane at low concentrations. The resulting shift was smaller (0.009 ppm/mM) when compared with using higher TMSP concentrations as reference. This discrepancy might be due to additional dioxane–water interactions. Measurements with an external chloroform reference in a coaxial geometry showed a shift of −0.013 ppm/mM resulting from the opposing effects of macromolecules in water exchange‐induced shift and diamagnetic susceptibility shift. All these effects should be considered in the interpretation of tissue phase contrast. From the experimental data, the equilibrium binding constant between BSA and TMSP has been quantified to be Kd = 1.3 ± 0.4, and the estimated number of interaction sites for BSA is 12.7 ± 2.6. Magn Reson Med, 2013.

Integration of ultra-high field MRI and histology for connectome based research of brain disorders

Ultra-high field magnetic resonance imaging (MRI) became increasingly relevant for in vivo neuroscientific research because of improved spatial resolutions. However, this is still the unchallenged domain of histological studies, which long played an important role in the investigation of neuropsychiatric disorders. While the field of biological psychiatry strongly advanced on macroscopic levels, current developments are rediscovering the richness of immunohistological information when attempting a multi-level systematic approach to brain function and dysfunction. For most studies, histology sections lost information on three-dimensional reconstructions. Translating histological sections to 3D-volumes would thus not only allow for multi-stain and multi-subject alignment in post mortem data, but also provide a crucial step in big data initiatives involving the network analyses currently performed with in vivo MRI. We therefore investigated potential pitfalls during integration of MR and histological information where no additional blockface information is available. We demonstrated that strengths and requirements from both methods can be effectively combined at a spatial resolution of 200 μm. However, the success of this approach is heavily dependent on choices of hardware, sequence and reconstruction. We provide a fully automated pipeline that optimizes histological 3D reconstructions, providing a potentially powerful solution not only for primary human post mortem research institutions in neuropsychiatric research, but also to help alleviate the massive workloads in neuroanatomical atlas initiatives. We further demonstrate (for the first time) the feasibility and quality of ultra-high spatial resolution (150 μm isotopic) imaging of the entire human brain MRI at 7T, offering new opportunities for analyses on MR-derived information.