Our main research interest is developing engineering approaches to study the brain. The current focuses are in three areas: 1) developing non-invasive MRI techniques for visualizing human brain structure and function, 2) developing non-invasive remote cell modulation techniques to modulate neuronal activity and 3) applications to the understanding and treatment of neurodegenerative diseases.

Remote Cell Modulation using Electromagnetic Fields

Pharmacologic intervention and electrophysiology are two classical methods for modulating cell membrane permeability to various ions. Pharmacological intervention uses chemical compounds; electrophysiology uses minute electrodes or patch clamps to apply electrical potential cross cell membrane. The former lacks cellular specificity and may create many confounding effects; the latter is difficult to apply to multiple cells and is highly invasive. Optogenetics is a technique that uses light to activate and suppress cell activities via optical interaction with engineered light sensitive channel proteins such as channelrhodopsin. While optogenetics has proved to be an extremely powerful technique, light does not penetrate biological tissue well. We are developing a method that uses electromagnetic fields together with engineering membrane proteins to modulate cell activities. In one example, we fuse temperature sensitive membrane proteins such as the transient receptor potential channels (e.g. TRPV1) with a small ferritin-binding domain 5 (D5) of kininogen-1. These fusion proteins result in endogenous Ferritin-iron Redistribution to Ion Channels (FeRIC). These ion-channel-bound ferritins interact with applied RF waves, which triggers calcium influx through TRPV1 channels. In one application, we used FeRIC to transiently activate TRPV1 or TRPV4 in neural crest cells in chick embryos to mimic fever-induced stimulation of these channels. TRPV1 or TRPV4 activation resulted in cardiac and craniofacial birth defects similar to those induced by fever. These results suggest that preventing TRPV1 and TRPV4 activation during first trimester febrile episodes may reduce the incidence of common forms of birth defects.

FeRIC mimics heart defects

Hutson, M. R., Keyte, A. L., Hernández-Morales, M., Gibbs, et al. (2017). Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects. Sci. Signal., 10(500), eaal4055.
CNN, Oct 10, 2017: How fever in early pregnancy can cause birth defects.
Hernández-Morales, M., Shang, T., Chen, J., Han, V., & Liu, C. (2020). Lipid Oxidation Induced by RF Waves and Mediated by Ferritin Iron Causes Activation of Ferritin-Tagged Ion Channels. Cell reports, 30(10), 3250-3260.

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is a non-invasive technology for imaging human body. It is used daily in hospitals for aiding medical diagnosis; it is also widely used for studying human brain structure and function. Our lab develops methods to improve existing MRI techniques or create new forms of MRI for improving medical diagnosis and our understanding of human brain. We are broadly interested in all things related to MRI. The following are a few examples of projects we are working on.

Imaging and quantifying magnetic susceptibility

Magnetic susceptibility is a physical quantity that defines how strongly a material can be magnetized by an applied magnetic field. While classical magnetometers or SQUID detectors can measure bulk magnetic susceptibility, they do not measure the anatomical distribution of magnetic susceptibility inside the human body. We are developing MRI-based methods to measure the spatial distribution of magnetic susceptibility in biological tissues. This is possible because magnetic susceptibility changes the spatial pattern of magnetic field which in turn changes the frequency of MRI signal. These methods are now generally called quantitative susceptibility mapping (QSM) and susceptibility tensor imaging (STI). QSM and STI use the phase information of gradient echo MRI to produce high-resolution 3D maps of magnetic susceptibility which reflect the local molecular contents and tissue architecture. QSM and STI have been used to quantify tissue iron stores, calcification, myelination in white matter and the dynamic conversion between oxy- and deoxyhemoglobin. By quantifying magnetic susceptibility anisotropy, STI allows the mapping of the orientations of axonal fiber, myofiber and collagen.

QSM STI Examples


Liu, C., Li, W., Tong, K. A., Yeom, K. W., & Kuzminski, S. (2015). Susceptibility‐weighted imaging and quantitative susceptibility mapping in the brain. Journal of magnetic resonance imaging, 42(1), 23-41.

Imaging and quantifying molecular diffusion

MRI is the only technique that can image and quantify molecular diffusion inside the human body non-invasively. Knowing the properties of molecular diffusion can tell us information about tissue microstructure as molecular movement is affected by various biological membranes and cell density. We are developing image acquisition and reconstruction techniques to generate high quality diffusion-weighted images. We are also developing mathematical models to relate diffusion-weighted MRI signals to the underlying tissue properties. For example, we have pioneered the method to use higher order tensors to characterize non-Gaussian diffusion observed in biological tissues. These higher order tensors include covariance tensor (2nd order), skewness tensor (3rd order), kurtosis tensor (4th order) and so on.

Higher Order Tensor Diffusion


Liu, C., et al. Generalized diffusion tensor imaging (GDTI) using higher-order tensor (HOT) statistics. 11th ISMRM, Toronto, 2003. p 242
Liu, C., Bammer, R., & Moseley, M. E. (2003). Generalized Diffusion Tensor Imaging (GDTI): A Method for Characterizing and Imaging Diffusion Anisotropy Caused by Non‐Gaussian Diffusion. Israel Journal of Chemistry, 43(1‐2), 145-154.
Liu, C., Bammer, R., Acar, B., & Moseley, M. E. (2004). Characterizing non‐Gaussian diffusion by using generalized diffusion tensors. Magnetic Resonance in Medicine, 51(5), 924-937. 

Ultra-high field MRI

We are involved in a project funded by NIH BRAIN Initiative to develop a next-generation human brain MRI scanner that utilizes 7-Tesla magnetic field.

Berkeley News, Oct 6, 2017

Multiphoton MRI

Today’s MRI assumes single‐photon excitation.1 That is, for each nuclear spin, a single photon accompanies the transition between energy states. This photon must resonate near the Larmor frequency. Here, we show that, instead of the usual single‐photon resonance, we can excite multiphoton resonances to generate signal for MRI by using multiple magnetic field frequencies, none of which is near the Larmor frequency. Only the total energy absorbed by a spin must correspond to the Larmor frequency.

Multiphoton MRI
Han, Victor, and Chunlei Liu. "Multiphoton magnetic resonance in imaging: A classical description and implementation." Magnetic Resonance in Medicine (2020).
Victor Han,  Finalist for 2020 ISMRM I.I. Rabi Award for work in multiphoton MRI.

Neurodegeneration - Parkinson's and Alzheimer's

Neurodegeneration refers to the progressive atrophy and loss of function of neurons, which is present in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The technologies we develop have been applied to improve the understanding, diagnosis and treatment of these diseases. For example, the susceptibility MRI techniques are used for studying aggregation of pathological proteins and detecting structural and functional changes, and for deep brain stimulation surgical planning. 

PD-AD

Guan, X., Xuan, M., Gu, Q., Huang, P., Liu, C., Wang, N., ... & Zhang, M. (2017). Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping. NMR in Biomedicine, 30(4), e3489.
He, N., Huang, P., Ling, H., Langley, J., Liu, C., Ding, B., ... & Hu, X. (2017). Dentate nucleus iron deposition is a potential biomarker for tremor‐dominant Parkinson's disease. NMR in Biomedicine, 30(4), e3554.
Guan, X., Huang, P., Zeng, Q., Liu, C., Wei, H., Xuan, M., ... & Luo, X. (2019). Quantitative susceptibility mapping as a biomarker for evaluating white matter alterations in Parkinson’s disease. Brain imaging and behavior, 13(1), 220-231.
He, N., Ling, H., Ding, B., Huang, J., Zhang, Y., Zhang, Z., ... & Yan, F. (2015). Region‐specific disturbed iron distribution in early idiopathic P arkinson's disease measured by quantitative susceptibility mapping. Human brain mapping, 36(11), 4407-4420.
Guan, X., Zhang, Y., Wei, H., Guo, T., Zeng, Q., Zhou, C., ... & Xu, X. (2019). Iron-related nigral degeneration influences functional topology mediated by striatal dysfunction in Parkinson's disease. Neurobiology of aging, 75, 83-97.
Guan, X., Guo, T., Zhou, C., Wu, J., Gao, T., Bai, X., ... & Huang, P. (2020). Asymmetrical nigral iron accumulation in Parkinson’s disease with motor asymmetry: an explorative, longitudinal and test-retest study. Aging (Albany NY), 12(18), 18622.
Gong, N. J., Dibb, R., Bulk, M., van der Weerd, L., & Liu, C. (2019). Imaging beta amyloid aggregation and iron accumulation in Alzheimer's disease using quantitative susceptibility mapping MRI. Neuroimage, 191, 176-185.
Gong, N. J., Chan, C. C., Leung, L. M., Wong, C. S., Dibb, R., & Liu, C. (2017). Differential microstructural and morphological abnormalities in mild cognitive impairment and A lzheimer's disease: Evidence from cortical and deep gray matter. Human brain mapping, 38(5), 2495-2508.
Li, W., Langkammer, C., Chou, Y. H., Petrovic, K., Schmidt, R., Song, A. W., ... & Liu, C. (2015). Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults. Neuroimage, 105, 45-52.
Wei, H., Zhang, C., Wang, T., He, N., Li, D., Zhang, Y., ... & Sun, B. (2019). Precise targeting of the globus pallidus internus with quantitative susceptibility mapping for deep brain stimulation surgery. Journal of Neurosurgery, 1(aop), 1-7.
Li, J., Li, Y., Gutierrez, L., Xu, W., Wu, Y., Liu, C., ... & Wei, H. (2020). Imaging the Centromedian Thalamic Nucleus Using Quantitative Susceptibility Mapping. Frontiers in Human Neuroscience, 13, 447.
Guan, X., Guo, T., Zeng, Q., Wang, J., Zhou, C., Liu, C., ... & Xu, X. (2019). Oscillation-specific nodal alterations in early to middle stages Parkinson’s disease. Translational Neurodegeneration, 8(1), 36.