The Lee Lab uses interdisciplinary approaches from biology and engineering to analyze, debug, and manipulate systems-level brain circuits. We seek to understand the connectivity and function of these large-scale networks in order to drive the development of new therapies for neurological diseases. This research finds its basic building blocks in areas ranging from medical imaging and signal processing to genetics and molecular biology.

Dr. Lee is a recipient of the 2010 NIH/NIBIB R00 Award, the 2010 NIH Director's New Innovator Award, the 2010 Okawa Foundation Research Grant Award, the 2011 NSF CAREER Award, the 2012 Alfred P. Sloan Foundation Research Fellowship Award, and the 2013 Alzheimer's Association New Investigator Award.

Academic Appointments

Honors & Awards

  • NIH/NIBIB K99/R00 Award, NIH/NIBIB (2008/2010)
  • NIH Director's New Innovator Award, NIH (2010)
  • Okawa Foundation Research Grant Award, Okawa Foundation (2010)
  • NSF CAREER Award, NSF (2011)
  • Alfred P. Sloan Foundation Research Fellowship, Alfred P. Sloan Foundation (2012)
  • Epilepsy Therapy Project Award, Epilepsy Foundation (2012)
  • Alzheimer's Association New Investigator Award, Alzheimer's Association (2013)
  • NIH/NIA RF1: Study of Alzheimer's Disease, NIH/NIA (2014)
  • NIH/NINDS R01: Study of Traumatic Brain Injury, NIH/NINDS (2014)
  • Stanford Bio-X interdisciplinary seed grant, Stanford Bio-X (2014)
  • NIH/NINDS R01: Study of Basal Ganglia Circuit Dynamics, NIH/NINDS (2015)

Professional Education

  • BS, Seoul National University, Electrical Engineering
  • MS, Stanford University, Electrical Engineering
  • PhD, Stanford University, Electrical Engineering (2004)

Current Research and Scholarly Interests

In vivo visualization and control of neural circuits

2016-17 Courses

Stanford Advisees

Graduate and Fellowship Programs

All Publications

  • Comparison of fMRI analysis methods for heterogeneous BOLD responses in block design studies. NeuroImage Liu, J., Duffy, B. A., Bernal-Casas, D., Fang, Z., Lee, J. H. 2017; 147: 390-408


    A large number of fMRI studies have shown that the temporal dynamics of evoked BOLD responses can be highly heterogeneous. Failing to model heterogeneous responses in statistical analysis can lead to significant errors in signal detection and characterization and alter the neurobiological interpretation. However, to date it is not clear that, out of a large number of options, which methods are robust against variability in the temporal dynamics of BOLD responses in block-design studies. Here, we used rodent optogenetic fMRI data with heterogeneous BOLD responses and simulations guided by experimental data as a means to investigate different analysis methods' performance against heterogeneous BOLD responses. Evaluations are carried out within the general linear model (GLM) framework and consist of standard basis sets as well as independent component analysis (ICA). Analyses show that, in the presence of heterogeneous BOLD responses, conventionally used GLM with a canonical basis set leads to considerable errors in the detection and characterization of BOLD responses. Our results suggest that the 3rd and 4th order gamma basis sets, the 7th to 9th order finite impulse response (FIR) basis sets, the 5th to 9th order B-spline basis sets, and the 2nd to 5th order Fourier basis sets are optimal for good balance between detection and characterization, while the 1st order Fourier basis set (coherence analysis) used in our earlier studies show good detection capability. ICA has mostly good detection and characterization capabilities, but detects a large volume of spurious activation with the control fMRI data.

    View details for DOI 10.1016/j.neuroimage.2016.12.045

    View details for PubMedID 27993672

  • Studying Brain Circuit Function with Dynamic Causal Modeling for Optogenetic fMRI. Neuron Bernal-Casas, D., Lee, H. J., Weitz, A. J., Lee, J. H. 2017; 93 (3): 522-532 e5


    Defining the large-scale behavior of brain circuits with cell type specificity is a major goal of neuroscience. However, neuronal circuit diagrams typically draw upon anatomical and electrophysiological measurements acquired in isolation. Consequently, a dynamic and cell-type-specific connectivity map has never been constructed from simultaneous measurements across the brain. Here, we introduce dynamic causal modeling (DCM) for optogenetic fMRI experiments-which uniquely allow cell-type-specific, brain-wide functional measurements-to parameterize the causal relationships among regions of a distributed brain network with cell type specificity. Strikingly, when applied to the brain-wide basal ganglia-thalamocortical network, DCM accurately reproduced the empirically observed time series, and the strongest connections were key connections of optogenetically stimulated pathways. We predict that quantitative and cell-type-specific descriptions of dynamic connectivity, as illustrated here, will empower novel systems-level understanding of neuronal circuit dynamics and facilitate the design of more effective neuromodulation therapies.

    View details for DOI 10.1016/j.neuron.2016.12.035

    View details for PubMedID 28132829

  • High spatial resolution compressed sensing (HSPARSE) functional MRI. Magnetic resonance in medicine Fang, Z., Van Le, N., Choy, M., Lee, J. H. 2016; 76 (2): 440-455


    To propose a novel compressed sensing (CS) high spatial resolution functional MRI (fMRI) method and demonstrate the advantages and limitations of using CS for high spatial resolution fMRI.A randomly undersampled variable density spiral trajectory enabling an acceleration factor of 5.3 was designed with a balanced steady state free precession sequence to achieve high spatial resolution data acquisition. A modified k-t SPARSE method was then implemented and applied with a strategy to optimize regularization parameters for consistent, high quality CS reconstruction.The proposed method improves spatial resolution by six-fold with 12 to 47% contrast-to-noise ratio (CNR), 33 to 117% F-value improvement and maintains the same temporal resolution. It also achieves high sensitivity of 69 to 99% compared the original ground-truth, small false positive rate of less than 0.05 and low hemodynamic response function distortion across a wide range of CNRs. The proposed method is robust to physiological noise and enables detection of layer-specific activities in vivo, which cannot be resolved using the highest spatial resolution Nyquist acquisition.The proposed method enables high spatial resolution fMRI that can resolve layer-specific brain activity and demonstrates the significant improvement that CS can bring to high spatial resolution fMRI. Magn Reson Med 76:440-455, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

    View details for DOI 10.1002/mrm.25854

    View details for PubMedID 26511101

  • Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses. Neuron Lee, H. J., Weitz, A. J., Bernal-Casas, D., Duffy, B. A., Choy, M., Kravitz, A. V., Kreitzer, A. C., Lee, J. H. 2016; 91 (2): 412-424


    A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with-though not easily predicted from-contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal.

    View details for DOI 10.1016/j.neuron.2016.06.010

    View details for PubMedID 27373834

  • Combining optogenetic stimulation and fMRI to validate a multivariate dynamical systems model for estimating causal brain interactions NEUROIMAGE Ryali, S., Shih, Y. I., Chen, T., Kochalka, J., Albaugh, D., Fang, Z., Supekar, K., Lee, J. H., Menon, V. 2016; 132: 398-405


    State-space multivariate dynamical systems (MDS) (Ryali et al. 2011) and other causal estimation models are being increasingly used to identify directed functional interactions between brain regions. However, the validity and accuracy of such methods are poorly understood. Performance evaluation based on computer simulations of small artificial causal networks can address this problem to some extent, but they often involve simplifying assumptions that reduce biological validity of the resulting data. Here, we use a novel approach taking advantage of recently developed optogenetic fMRI (ofMRI) techniques to selectively stimulate brain regions while simultaneously recording high-resolution whole-brain fMRI data. ofMRI allows for a more direct investigation of causal influences from the stimulated site to brain regions activated downstream and is therefore ideal for evaluating causal estimation methods in vivo. We used ofMRI to investigate whether MDS models for fMRI can accurately estimate causal functional interactions between brain regions. Two cohorts of ofMRI data were acquired, one at Stanford University and the University of California Los Angeles (Cohort 1) and the other at the University of North Carolina Chapel Hill (Cohort 2). In each cohort, optical stimulation was delivered to the right primary motor cortex (M1). General linear model analysis revealed prominent downstream thalamic activation in Cohort 1, and caudate-putamen (CPu) activation in Cohort 2. MDS accurately estimated causal interactions from M1 to thalamus and from M1 to CPu in Cohort 1 and Cohort 2, respectively. As predicted, no causal influences were found in the reverse direction. Additional control analyses demonstrated the specificity of causal interactions between stimulated and target sites. Our findings suggest that MDS state-space models can accurately and reliably estimate causal interactions in ofMRI data and further validate their use for estimating causal interactions in fMRI. More generally, our study demonstrates that the combined use of optogenetics and fMRI provides a powerful new tool for evaluating computational methods designed to estimate causal interactions between distributed brain regions.

    View details for DOI 10.1016/j.neuroimage.2016.02.067

    View details for Web of Science ID 000374832200039

    View details for PubMedID 26934644

  • Probing Neural Transplant Networks In Vivo with Optogenetics and Optogenetic fMRI STEM CELLS INTERNATIONAL Weitz, A. J., Lee, J. H. 2016


    Understanding how stem cell-derived neurons functionally integrate into the brain upon transplantation has been a long sought-after goal of regenerative medicine. However, methodological limitations have stood as a barrier, preventing key insight into this fundamental problem. A recently developed technology, termed optogenetic functional magnetic resonance imaging (ofMRI), offers a possible solution. By combining targeted activation of transplanted neurons with large-scale, noninvasive measurements of brain activity, ofMRI can directly visualize the effect of engrafted neurons firing on downstream regions. Importantly, this tool can be used to identify not only whether transplanted neurons have functionally integrated into the brain, but also which regions they influence and how. Furthermore, the precise control afforded over activation enables the input-output properties of engrafted neurons to be systematically studied. This review summarizes the efforts in stem cell biology and neuroimaging that made this development possible and outlines its potential applications for improving and optimizing stem cell-based therapies in the future.

    View details for DOI 10.1155/2016/8612751

    View details for Web of Science ID 000376335900001

    View details for PubMedID 27293449

  • Optogenetic Functional MRI. Journal of visualized experiments : JoVE Lin, P., Fang, Z., Liu, J., Lee, J. H. 2016


    The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional magnetic resonance imaging (ofMRI), which is a novel technique that combines the relatively high spatial resolution of high-field fMRI with the precision of optogenetic stimulation. Fiber optics that enable delivery of specific wavelengths of light deep into the brain in vivo are implanted into regions of interest in order to specifically stimulate targeted cell types that have been genetically induced to express light-sensitive trans-membrane conductance channels, called opsins. fMRI is used to provide a non-invasive method of determining the brain's global dynamic response to optogenetic stimulation of specific neural circuits through measurement of the blood-oxygen-level-dependent (BOLD) signal, which provides an indirect measurement of neuronal activity. This protocol describes the construction of fiber optic implants, the implantation surgeries, the imaging with photostimulation and the data analysis required to successfully perform ofMRI. In summary, the precise stimulation and whole-brain monitoring ability of ofMRI are crucial factors in making ofMRI a powerful tool for the study of the connectomics of the brain in both healthy and diseased states.

    View details for DOI 10.3791/53346

    View details for PubMedID 27167840

  • Frequency-selective control of cortical and subcortical networks by central thalamus ELIFE Liu, J., Lee, H. J., Weitz, A. J., Fang, Z., Lin, P., Choy, M., Fisher, R., Pinskiy, V., Tolpygo, A., Mitra, P., Schiff, N., Lee, J. H. 2015; 4
  • MRI compatible optrodes for simultaneous LFP and optogenetic fMRI investigation of seizure-like afterdischarges. NeuroImage Duffy, B. A., Choy, M., Chuapoco, M. R., Madsen, M., Lee, J. H. 2015; 123: 173-184


    In preclinical studies, implanted electrodes can cause severe degradation of MRI images and hence are seldom used for chronic studies employing functional magnetic resonance imaging. In this study, we developed carbon fiber optrodes (optical fiber and electrode hybrid devices), which can be utilised in chronic longitudinal studies aiming to take advantage of emerging optogenetic technologies, and compared them with the more widely used tungsten optrodes. We find that optrodes constructed using small diameter (~130 μm) carbon fiber electrodes cause significantly reduced artifact on functional MRI images compared to those made with 50 μm diameter tungsten wire and at the same time the carbon electrodes have lower impedance, which leads to higher quality LFP recordings. In order to validate this approach, we use these devices to study optogenetically-induced seizure-like afterdischarges in rats sedated with dexmedetomidine and compare these to sub (seizure) threshold stimulations in the same animals. The results indicate that seizure-like afterdischarges involve several extrahippocampal brain regions that are not recruited by subthreshold optogenetic stimulation of the hippocampus at 20 Hz. Subthreshold stimulation led to activation of the entire ipsilateral hippocampus and septum, whereas afterdischarges additionally produced activations in the contralateral hippocampal formation, neocortex, cerebellum, nucleus accumbens, and thalamus. Although we demonstrate just one application, given the ease of fabrication, we anticipate that carbon fiber optrodes could be utilised in a variety of studies that could benefit from longitudinal optogenetic functional magnetic resonance imaging.

    View details for DOI 10.1016/j.neuroimage.2015.07.038

    View details for PubMedID 26208873

  • Direct in vivo assessment of human stem cell graft-host neural circuits NEUROIMAGE Byers, B., Lee, H. J., Liu, J., Weitz, A. J., Lin, P., Zhang, P., Shcheglovitov, A., Dolmetsch, R., Pera, R. R., Lee, J. H. 2015; 114: 328-337


    Despite the potential of stem cell-derived neural transplants for treating intractable neurological diseases, the global effects of a transplant's electrical activity on host circuitry have never been measured directly, preventing the systematic optimization of such therapies. Here, we overcome this problem by combining optogenetics, stem cell biology, and neuroimaging to directly map stem cell-driven neural circuit formation in vivo. We engineered human induced pluripotent stem cells (iPSCs) to express channelrhodopsin-2 and transplanted resulting neurons to striatum of rats. To non-invasively visualize the function of newly formed circuits, we performed high-field functional magnetic resonance imaging (fMRI) during selective stimulation of transplanted cells. fMRI successfully detected local and remote neural activity, enabling the global graft-host neural circuit function to be assessed. These results demonstrate the potential of a novel neuroimaging-based platform that can be used to identify how a graft's electrical activity influences the brain network in vivo.

    View details for DOI 10.1016/j.neuroimage.2015.03.079

    View details for Web of Science ID 000355002900030

    View details for PubMedID 25936696

  • Reduction of Surface Roughness in Epitaxially Grown Germanium by Controlled Thermal Oxidation IEEE ELECTRON DEVICE LETTERS Jung, W., Nam, J. H., Pal, A., Lee, J. H., Na, Y., Kim, Y., Lee, J. H., Saraswat, K. C. 2015; 36 (4): 297-299
  • Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations. NeuroImage Weitz, A. J., Fang, Z., Lee, H. J., Fisher, R. S., Smith, W. C., Choy, M., Liu, J., Lin, P., Rosenberg, M., Lee, J. H. 2015; 107: 229-241


    Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

    View details for DOI 10.1016/j.neuroimage.2014.10.039

    View details for PubMedID 25462689

  • In vivo imaging of transplanted stem cells in the central nervous system. Current opinion in genetics & development Duffy, B. A., Weitz, A. J., Lee, J. H. 2014; 28: 83-88


    In vivo imaging is increasingly being utilized in studies investigating stem cell-based treatments for neurological disorders. Direct labeling is used in preclinical and clinical studies to track the fate of transplanted cells. To further determine cell viability, experimental studies are able to take advantage of reporter gene technologies. Structural and functional brain imaging can also be used alongside cell imaging as biomarkers of treatment efficacy. Furthermore, it is possible that new imaging techniques could be used to monitor functional integration of stem cell-derived cells with the host nervous system. In this review, we examine recent developments in these areas and identify promising directions for future research at the interface of stem cell therapies and neuroimaging.

    View details for DOI 10.1016/j.gde.2014.09.007

    View details for PubMedID 25461455

  • High-throughput optogenetic functional magnetic resonance imaging with parallel computations JOURNAL OF NEUROSCIENCE METHODS Fang, Z., Lee, J. H. 2013; 218 (2): 184-195


    Optogenetic functional magnetic resonance imaging (of MRI) technology enables cell-type-specific, temporally precise neuronal control and the accurate, in vivo readout of the resulting activity across the entire brain. With the ability to precisely control excitation and inhibition parameters and accurately record the resulting activity, there is an increased need for a high-throughput method to bring the of MRI studies to their full potential. In this paper, an advanced system facilitating real-time fMRI with interactive control and analysis in a fraction of the MRI acquisition repetition time (TR) is proposed. With high-processing speed, sufficient time will be available for the integration of future developments that further enhance of MRI data or streamline the study. We designed and implemented a highly optimised, massively parallel system using graphics processing units (GPUs), which achieves the reconstruction, motion correction, and analysis of 3D volume data in approximately 12.80 ms. As a result, with a 750 ms TR and 4 interleaf fMRI acquisition, we can now conduct sliding window reconstruction, motion correction, analysis and display in approximately 1.7% of the TR. Therefore, a significant amount of time can now be allocated to integrating advanced but computationally intensive methods that improve image quality and enhance the analysis results within a TR. Utilising the proposed high-throughput imaging platform with sliding window reconstruction, we were also able to observe the much-debated initial dips in our of MRI data. Combined with methods to further improve SNR, the proposed system will enable efficient real-time, interactive, high-throughput of MRI studies.

    View details for DOI 10.1016/j.jneumeth.2013.04.015

    View details for Web of Science ID 000324084400006

    View details for PubMedID 23747482

  • Informing brain connectivity with optogenetic functional magnetic resonance imaging NEUROIMAGE Lee, J. H. 2012; 62 (4): 2244-2249


    Optogenetic functional magnetic resonance imaging (ofMRI) is a novel approach that combines optogenetic control of neural circuits with high-field functional MRI. Optogenetics is a neuro-modulation technology in which light-activated trans-membrane conductance regulators are introduced into specifically targeted cell types to allow temporally precise, millisecond-scale activity modulation in vivo. By combining optogenetic control with fMRI readout, neural activity arising from specific circuit elements defined by genetic identity, cell body location, and axonal projection targets can be monitored in vivo across the whole brain. These unique features of ofMRI open new vistas for in vivo characterization of the dense plexus of neural connections according to their type and functionality.

    View details for DOI 10.1016/j.neuroimage.2012.01.116

    View details for Web of Science ID 000308265200008

    View details for PubMedID 22326987

  • Methods for registration of magnetic resonance images of ex vivo prostate specimens with histology JOURNAL OF MAGNETIC RESONANCE IMAGING Kimm, S. Y., Tarin, T. V., Lee, J. H., Hu, B., Jensen, K., Nishimura, D., Brooks, J. D. 2012; 36 (1): 206-212


    To evaluate two methods of scanning and tissue processing to achieve accurate magnetic resonance (MR)-histologic correlation in human prostate specimens.Two prostates had acrylic paint markers injected to define the plane of imaging and serve as internal fiducials. Each was placed on a polycarbonate plane-finder device (PFD), which was adjusted to align the imaging and cutting planes. Three prostates were aligned by use of a plane finder key (PFK), a polycarbonate plate that locks the specimen in a cylindrical carrier. Markers were injected for registration analysis. Prostates were imaged, then sectioned. Imaging software was used to create registration maps of the MR and histology images. Measurements between control points were made and compared.Accurate correlation was achieved between MR and histologic images. The mean displacement (MD) between the corresponding registration points using the PFD technique ranged from 1.11-1.38 mm for each section. The MD for all sections was 1.24 mm. The MD using the PFK technique ranged from 0.79-1.01 mm for each section, and the MD across all sections for the PFK was 0.92 mm.We describe two methods that can achieve accurate, reproducible correlation between MR imaging and histologic sections in human prostatectomy specimens.

    View details for DOI 10.1002/jmri.23614

    View details for Web of Science ID 000305185700021

    View details for PubMedID 22359365

  • Analysis of the BOLD characteristics in pass-band bSSFP fMRI INTERNATIONAL JOURNAL OF IMAGING SYSTEMS AND TECHNOLOGY Kim, T. S., Lee, J., Lee, J. H., Glover, G. H., Pauly, J. M. 2012; 22 (1): 23-32

    View details for DOI 10.1002/ima.21296

    View details for Web of Science ID 000300505200004

  • SNR Dependence of Optimal Parameters for Apparent Diffusion Coefficient Measurements IEEE TRANSACTIONS ON MEDICAL IMAGING Saritas, E. U., Lee, J. H., Nishimura, D. G. 2011; 30 (2): 424-437


    Optimizing the diffusion-weighted imaging (DWI) parameters (i.e., the b-value and the number of image averages) to the tissue of interest is essential for producing high-quality apparent diffusion coefficient (ADC) maps. Previous investigation of this optimization was performed assuming Gaussian noise statistics for the ADC map, which is only valid for high signal-to-noise ratio (SNR) imaging. In this work, the true statistics of the noise in ADC maps are derived, followed by an optimization of the DWI parameters as a function of the imaging SNR. Specifically, it is demonstrated that the optimum b-value is a monotonically increasing function of the imaging SNR, which converges to the optimum b-value from previously proposed approaches for high-SNR cases, while exhibiting a significant deviation from this asymptote for low-SNR situations. Incorporating the effects of T(2) weighting further increases the SNR dependence of the optimal parameters. The proposed optimization scheme is particularly important for high-resolution DWI, which intrinsically suffers from low SNR and therefore cannot afford the use of the conventional high b-values. Comparison scans were performed for high-resolution DWI of the spinal cord, demonstrating the improvements in the resulting images and the ADC maps achieved by this method.

    View details for DOI 10.1109/TMI.2010.2084583

    View details for Web of Science ID 000286931000022

    View details for PubMedID 20934948

  • Tracing activity across the whole brain neural network with optogenetic functional magnetic resonance imaging. Frontiers in neuroinformatics Lee, J. H. 2011; 5: 21-?


    Despite the overwhelming need, there has been a relatively large gap in our ability to trace network level activity across the brain. The complex dense wiring of the brain makes it extremely challenging to understand cell-type specific activity and their communication beyond a few synapses. Recent development of the optogenetic functional magnetic resonance imaging (ofMRI) provides a new impetus for the study of brain circuits by enabling causal tracing of activities arising from defined cell types and firing patterns across the whole brain. Brain circuit elements can be selectively triggered based on their genetic identity, cell body location, and/or their axonal projection target with temporal precision while the resulting network response is monitored non-invasively with unprecedented spatial and temporal accuracy. With further studies including technological innovations to bring ofMRI to its full potential, ofMRI is expected to play an important role in our system-level understanding of the brain circuit mechanism.

    View details for DOI 10.3389/fninf.2011.00021

    View details for PubMedID 22046160

  • Global and local fMRI signals driven by neurons defined optogenetically by type and wiring NATURE Lee, J. H., Durand, R., Gradinaru, V., Zhang, F., Goshen, I., Kim, D., Fenno, L. E., Ramakrishnan, C., Deisseroth, K. 2010; 465 (7299): 788-792


    Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD) signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications. Using a novel integrated technology unifying optogenetic control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIalpha-expressing excitatory neurons, either in the neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (of MRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that of MRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations and fMRI with electrical stimulation that will also directly drive afferent and nearby axons, this of MRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-used fMRI BOLD signal, and the features of of MRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.

    View details for DOI 10.1038/nature09108

    View details for Web of Science ID 000278551800047

    View details for PubMedID 20473285

  • High-Contrast In Vivo Visualization of Microvessels Using Novel FeCo/GC Magnetic Nanocrystals MAGNETIC RESONANCE IN MEDICINE Lee, J. H., Sherlock, S. P., Terashima, M., Kosuge, H., Suzuki, Y., Goodwin, A., Robinson, J., Seo, W. S., Liu, Z., Luong, R., McConnell, M. V., Nishimura, D. G., Dai, H. 2009; 62 (6): 1497-1509


    FeCo-graphitic carbon shell nanocrystals are a novel MRI contrast agent with unprecedented high per-metal-atom-basis relaxivity (r(1) = 97 mM(-1) sec(-1), r(2) = 400 mM(-1) sec(-1)) and multifunctional capabilities. While the conventional gadolinium-based contrast-enhanced angiographic magnetic MRI has proven useful for diagnosis of vascular diseases, its short circulation time and relatively low sensitivity render high-resolution MRI of morphologically small vascular structures such as those involved in collateral, arteriogenic, and angiogenic vessel formation challenging. Here, by combining FeCo-graphitic carbon shell nanocrystals with high-resolution MRI technique, we demonstrate that such microvessels down to approximately 100 mum can be monitored in high contrast and noninvasively using a conventional 1.5-T clinical MRI system, achieving a diagnostic imaging standard approximating that of the more invasive X-ray angiography. Preliminary in vitro and in vivo toxicity study results also show no sign of toxicity.

    View details for DOI 10.1002/mrm.22132

    View details for Web of Science ID 000272067600017

    View details for PubMedID 19859938

  • Non-contrast-Enhanced Flow-Independent Peripheral MR Angiography with Balanced SSFP MAGNETIC RESONANCE IN MEDICINE Cukur, T., Lee, J. H., Bangerter, N. K., Hargreaves, B. A., Nishimura, D. G. 2009; 61 (6): 1533-1539


    Flow-independent angiography is a non-contrast-enhanced technique that can generate vessel contrast even with reduced blood flow in the lower extremities. A method is presented for producing these angiograms with magnetization-prepared balanced steady-state free precession (bSSFP). Because bSSFP yields bright fat signal, robust fat suppression is essential for detailed depiction of the vasculature. Therefore, several strategies have been investigated to improve the reliability of fat suppression within short scan times. Phase-sensitive SSFP can efficiently suppress fat; however, partial volume effects due to fat and water occupying the same voxel can lead to the loss of blood signal. In contrast, alternating repetition time (ATR) SSFP minimizes this loss; however, the level of suppression is compromised by field inhomogeneity. Finally, a new double-acquisition ATR-SSFP technique reduces this sensitivity to off-resonance. In vivo results indicate that the two ATR-based techniques provide more reliable contrast when partial volume effects are significant.

    View details for DOI 10.1002/mrm.21921

    View details for Web of Science ID 000266429900031

    View details for PubMedID 19365850

  • Fat/Water Separation Using a Concentric Rings Trajectory MAGNETIC RESONANCE IN MEDICINE Wu, H. H., Lee, J. H., Nishimura, D. G. 2009; 61 (3): 639-649


    The concentric rings two-dimensional (2D) k-space trajectory enables flexible trade-offs between image contrast, signal-to-noise ratio (SNR), spatial resolution, and scan time. However, to realize these benefits for in vivo imaging applications, a robust method is desired to deal with fat signal in the acquired data. Multipoint Dixon techniques have been shown to achieve uniform fat suppression with high SNR-efficiency for Cartesian imaging, but application of these methods for non-Cartesian imaging is complicated by the fact that fat off-resonance creates significant blurring artifacts in the reconstruction. In this work, two fat-water separation algorithms are developed for the concentric rings. A retracing design is used to sample rings near the center of k-space through multiple revolutions to characterize the fat-water phase evolution difference at multiple time points. This acquisition design is first used for multipoint Dixon reconstruction, and then extended to a spectroscopic approach to account for the trajectory's full evolution through 3D k-t space. As the trajectory is resolved in time, off-resonance effects cause shifts in frequency instead of spatial blurring in 2D k-space. The spectral information can be used to assess field variation and perform robust fat-water separation. In vivo experimental results demonstrate the effectiveness of both algorithms.

    View details for DOI 10.1002/mrm.21865

    View details for Web of Science ID 000263608300017

    View details for PubMedID 19097243

  • DWI of the spinal cord with reduced FOV single-shot EPI MAGNETIC RESONANCE IN MEDICINE Saritas, E. U., Cunningham, C. H., Lee, J. H., Han, E. T., Nishimura, D. G. 2008; 60 (2): 468-473


    Single-shot echo-planar imaging (ss-EPI) has not been used widely for diffusion-weighted imaging (DWI) of the spinal cord, because of the magnetic field inhomogeneities around the spine, the small cross-sectional size of the spinal cord, and the increased motion in that area due to breathing, swallowing, and cerebrospinal fluid (CSF) pulsation. These result in artifacts with the usually long readout duration of the ss-EPI method. Reduced field-of-view (FOV) methods decrease the required readout duration for ss-EPI, thereby enabling its practical application to imaging of the spine. In this work, a reduced FOV single-shot diffusion-weighted echo-planar imaging (ss-DWEPI) method is proposed, in which a 2D spatially selective echo-planar RF excitation pulse and a 180 degrees refocusing pulse reduce the FOV in the phase-encode (PE) direction, while suppressing the signal from fat simultaneously. With this method, multi slice images with higher in-plane resolutions (0.94 x 0.94 mm(2) for sagittal and 0.62 x 0.62 mm(2) for axial images) are achieved at 1.5 T, without the need for a longer readout.

    View details for DOI 10.1002/mrm.21640

    View details for Web of Science ID 000258105800029

    View details for PubMedID 18666126

  • Full-brain coverage and high-resolution Imaging capabilities of passband b-SSFP fMRI at 3T MAGNETIC RESONANCE IN MEDICINE Lee, J. H., Dumoulin, S. O., Saritas, E. U., Glover, G. H., Wandell, B. A., Nishimura, D. G., Pauly, J. M. 2008; 59 (5): 1099-1110


    Passband balanced-steady-state free precession (b-SSFP) fMRI is a recently developed method that utilizes the passband (flat portion) of the b-SSFP off-resonance response to measure MR signal changes elicited by changes in tissue oxygenation following increases in neuronal activity. Rapid refocusing and short readout durations of b-SSFP, combined with the relatively large flat portion of the b-SSFP off-resonance spectrum allows distortion-free full-brain coverage with only two acquisitions. This allows for high-resolution functional imaging, without the spatial distortion frequently encountered in conventional high-resolution functional images. Finally, the 3D imaging compatibility of the b-SSFP acquisitions permits isotropic-voxel-size high-resolution acquisitions. In this study we address some of the major technical issues involved in obtaining passband b-SSFP-based functional brain images with practical imaging parameters and demonstrate the advantages through breath-holding and visual field mapping experiments.

    View details for DOI 10.1002/mrm.21576

    View details for Web of Science ID 000255230700020

    View details for PubMedID 18421687

  • MRI using a concentric rings trajectory MAGNETIC RESONANCE IN MEDICINE Wu, H. H., Lee, J. H., Nishimura, D. G. 2008; 59 (1): 102-112


    The concentric rings two-dimensional (2D) k-space trajectory provides an alternative way to sample polar data. By collecting 2D k-space data in a series of rings, many unique properties are observed. The concentric rings are inherently centric-ordered, provide a smooth weighting in k-space, and enable shorter total scan times. Due to these properties, the concentric rings are well-suited as a readout trajectory for magnetization-prepared studies. When non-Cartesian trajectories are used for MRI, off-resonance effects can cause blurring and degrade the image quality. For the concentric rings, off-resonance blur can be corrected by retracing rings near the center of k-space to obtain a field map with no extra excitations, and then employing multifrequency reconstruction. Simulations show that the concentric rings exhibit minimal effects due to T(2) (*) modulation, enable shorter scan times for a Nyquist-sampled dataset than projection-reconstruction imaging or Cartesian 2D Fourier transform (2DFT) imaging, and have more spatially distributed flow and motion properties than Cartesian sampling. Experimental results show that off-resonance blurring can be successfully corrected to obtain high-resolution images. Results also show that concentric rings effectively capture the intended contrast in a magnetization-prepared sequence.

    View details for DOI 10.1002/mrm.21300

    View details for Web of Science ID 000251979600014

    View details for PubMedID 17969074

  • Synthesis and characterization of PVP-coated large core iron oxide nanoparticles as an MRI contrast agent. Nanotechnology 2008; 19 (16): 165101


    The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2∗ (reciprocal of T2∗ relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

    View details for DOI 10.1088/0957-4484/19/16/165101

    View details for PubMedID 21394237

  • FeCo/graphitic-shell nanocrystals as advanced magnetic-resonance-imaging and near-infrared agents NATURE MATERIALS Seo, W. S., Lee, J. H., Sun, X., Suzuki, Y., Mann, D., Liu, Z., Terashima, M., Yang, P. C., McConnell, M. V., Nishimura, D. G., Dai, H. 2006; 5 (12): 971-976


    Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

    View details for DOI 10.1038/nmat1775

    View details for Web of Science ID 000242478600021

    View details for PubMedID 17115025

  • Broadband multicoil imaging using multiple demodulation hardware: A feasibility study MAGNETIC RESONANCE IN MEDICINE Lee, J. H., Scott, G. C., Pauly, J. M., Nishimura, D. G. 2005; 54 (3): 669-676


    Multiple receiver-coil data collection is an effective approach to reduce scan time. There are many parallel imaging techniques that reduce scan time using multiple receiver coils. One of these methods, partially parallel imaging with localized sensitivities (PILS), utilizes the localized sensitivity of each coil. The advantages of PILS over other parallel imaging methods include the simplicity of the algorithm, good signal-to-noise ratio (SNR) properties, and the fact that there is no additional complexity involved in applying the algorithm to arbitrary k-space trajectories. This PILS method can be further improved to provide truly parallel broadband imaging with the use of multiple-demodulation hardware. By customizing the demodulation based on each coil's location, the k-space sampling rate can be chosen based on each coil's localized sensitivity region along the readout direction. A simulated demodulation of data from 2D Fourier transform (FT) and spiral trajectories is shown to demonstrate the method's feasibility.

    View details for DOI 10.1002/mrm.20595

    View details for Web of Science ID 000231494000018

    View details for PubMedID 16086362

  • Fast 3D imaging using variable-density spiral trajectories with applications to limb perfusion MAGNETIC RESONANCE IN MEDICINE Lee, J. H., Hargreaves, B. A., Hu, B. S., Nishimura, D. G. 2003; 50 (6): 1276-1285


    Variable-density k-space sampling using a stack-of-spirals trajectory is proposed for ultra fast 3D imaging. Since most of the energy of an image is concentrated near the k-space origin, a variable-density k-space sampling method can be used to reduce the sampling density in the outer portion of k-space. This significantly reduces scan time while introducing only minor aliasing artifacts from the low-energy, high-spatial-frequency components. A stack-of-spirals trajectory allows control over the density variations in both the k(x)-k(y) plane and the k(z) direction while fast k-space coverage is provided by spiral trajectories in the k(x)-k(y) plane. A variable-density stack-of-spirals trajectory consists of variable-density spirals in each k(x)-k(y) plane that are located in varying density in the k(z) direction. Phantom experiments demonstrate that reasonable image quality is preserved with approximately half the scan time. This technique was then applied to first-pass perfusion imaging of the lower extremities which demands very rapid volume coverage. Using a variable-density stack-of-spirals trajectory, 3D images were acquired at a temporal resolution of 2.8 sec over a large volume with a 2.5 x 2.5 x 8 mm(3) spatial resolution. These images were used to resolve the time-course of muscle intensity following contrast injection.

    View details for DOI 10.1002/mrm.10644

    View details for Web of Science ID 000186991500019

    View details for PubMedID 14648576

  • Noninvasive measurement of extraction fraction and single-kidney glomerular filtration rate with MR imaging in swine with surgically created renal artery stenoses RADIOLOGY Coulam, C. H., Lee, J. H., Wedding, K. L., Spielman, D. M., Pelc, N. J., Kee, S. T., Hill, B. B., Bouley, D. M., Derby, G. C., Myers, B. D., Sawyer-Glover, A. M., Sommer, F. G. 2002; 223 (1): 76-82


    To test whether magnetic resonance (MR) imaging enables accurate measurement of extraction fraction (EF) in swine with unilateral renal ischemia and to evaluate effects of renal arterial stenosis on EF and single-kidney glomerular filtration rate.High-grade unilateral renal arterial stenoses were surgically created in eight pigs. Direct measurements of renal venous and arterial inulin concentration provided reference standard estimates of single-kidney EF. Pigs were imaged with a 1.5-T imager to estimate EF, renal blood flow, and glomerular filtration rate. A breath-hold inversion-recovery spiral sequence was used to measure T1 of blood in the infrarenal inferior vena cava and renal veins after intravenous administration of gadopentetate dimeglumine, and these data were used to calculate EF. Cine-phase contrast material-enhanced imaging of the renal arteries provided quantitative renal blood flow measurements. Bilateral single-kidney glomerular filtration rate was then determined: glomerular filtration rate = renal blood flow x (1 - hematocrit level) x EF.A statistically significant linear correlation was found between EF, as determined with MR imaging, and inulin (r = 0.77). As compared with kidneys without renal arterial stenosis, kidneys with renal arterial stenosis showed 50% (0.14/0.28) EF reduction (P <.01) and 59% glomerular filtration rate reduction (P <.01).MR imaging shows promise for in vivo measurement of EF and glomerular filtration rate, which may be useful in assessing the clinical importance of renal arterial stenosis.

    View details for DOI 10.1148/radiol.2231010420

    View details for Web of Science ID 000174611900011

    View details for PubMedID 11930050