Publications by authors named "Zhongnan Fang"

10 Publications

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Diagnostic Accuracy of Quantitative Multi-Contrast 5-Minute Knee MRI Using Prospective Artificial Intelligence Image Quality Enhancement.

AJR Am J Roentgenol 2020 08 5. Epub 2020 Aug 5.

Department of Radiology, Stanford University, 1201 Welch Road, Stanford, California 94305, USA.

Background: Potential approaches for abbreviated knee MRI, including prospective acceleration with deep learning, have achieved limited clinical implementation to date.

Objectives: The objective of this study was to evaluate the inter-reader agreement of conventional knee MRI and a 5-minute 3D quantitative double-echo steady-state (qDESS) sequence with automatic T2 mapping and deep-learning super-resolution (DLSR) augmentation, as well as to compare the diagnostic performance of the two methods with respect to findings from arthroscopic surgery.

Methods: A total of 51 patients with knee pain underwent knee MRI that included an additional 3D qDESS sequence with automatic T2 mapping. Fourier interpolation was followed by prospective DLSR to enhance qDESS slice-resolution twofold. A musculoskeletal radiologist and a radiology resident performed retrospective independent evaluations of the articular cartilage, menisci, ligaments, bones, extensor mechanism, and synovium using conventional MRI. Following a two-month washout period, the readers reviewed qDESS images alone, followed by qDESS with the automatic T2 maps. Inter-reader agreement between conventional MRI and qDESS was computed using percent agreement and Cohen's Kappa. The sensitivity and specificity of conventional MRI, qDESS alone, and qDESS+T2 were compared with arthroscopic findings using exact McNemar's tests.

Results: Conventional MRI and qDESS demonstrated 92% agreement in evaluation of articular cartilage, menisci, ligaments, bones, extensor mechanism, and synovium combined. Kappa was 0.79 (0.76-0.81) across all imaging findings. In the 43/51 patients who underwent arthroscopy, sensitivity and specificity were not significantly different (p=0.23-1.00) between conventional MRI (sensitivity: 58%-93%; specificity: 27%-87%) and qDESS alone (sensitivity: 54%-90%; specificity: 23%-91%) for cartilage, menisci, ligaments, and synovium. Sensitivity and specificity for grade 1 cartilage lesions were 33%/56% for conventional MRI, 23%/53% for qDESS (p=0.81), and 46%/39% for qDESS+T2 (p=0.80); for grade 2A lesions, 27%/53% for conventional MRI, 26%/52% for qDESS (p=0.02), and 58%/40% for qDESS+T2 (p<0.001).

Conclusion: qDESS prospectively enhanced with deep learning had strong inter-reader agreement with conventional knee MRI and near-equivalent diagnostic performance with respect to arthroscopy. The ability of qDESS to automatically generate T2 maps increases sensitivity for cartilage abnormalities. Clinical Impact: qDESS using prospective artificial intelligence image quality enhancement may facilitate an abbreviated knee MRI protocol while generating quantitative T2 maps.
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August 2020

Utility of deep learning super-resolution in the context of osteoarthritis MRI biomarkers.

J Magn Reson Imaging 2020 03 16;51(3):768-779. Epub 2019 Jul 16.

Department of Radiology, Stanford University, Stanford, California, USA.

Background: Super-resolution is an emerging method for enhancing MRI resolution; however, its impact on image quality is still unknown.

Purpose: To evaluate MRI super-resolution using quantitative and qualitative metrics of cartilage morphometry, osteophyte detection, and global image blurring.

Study Type: Retrospective.

Population: In all, 176 MRI studies of subjects at varying stages of osteoarthritis.

Field Strength/sequence: Original-resolution 3D double-echo steady-state (DESS) and DESS with 3× thicker slices retrospectively enhanced using super-resolution and tricubic interpolation (TCI) at 3T.

Assessment: A quantitative comparison of femoral cartilage morphometry was performed for the original-resolution DESS, the super-resolution, and the TCI scans in 17 subjects. A reader study by three musculoskeletal radiologists assessed cartilage image quality, overall image sharpness, and osteophytes incidence in all three sets of scans. A referenceless blurring metric evaluated blurring in all three image dimensions for the three sets of scans.

Statistical Tests: Mann-Whitney U-tests compared Dice coefficients (DC) of segmentation accuracy for the DESS, super-resolution, and TCI images, along with the image quality readings and blurring metrics. Sensitivity, specificity, and diagnostic odds ratio (DOR) with 95% confidence intervals compared osteophyte detection for the super-resolution and TCI images, with the original-resolution as a reference.

Results: DC for the original-resolution (90.2 ± 1.7%) and super-resolution (89.6 ± 2.0%) were significantly higher (P < 0.001) than TCI (86.3 ± 5.6%). Segmentation overlap of super-resolution with the original-resolution (DC = 97.6 ± 0.7%) was significantly higher (P < 0.0001) than TCI overlap (DC = 95.0 ± 1.1%). Cartilage image quality for sharpness and contrast levels, and the through-plane quantitative blur factor for super-resolution images, was significantly (P < 0.001) better than TCI. Super-resolution osteophyte detection sensitivity of 80% (76-82%), specificity of 93% (92-94%), and DOR of 32 (22-46) was significantly higher (P < 0.001) than TCI sensitivity of 73% (69-76%), specificity of 90% (89-91%), and DOR of 17 (13-22).

Data Conclusion: Super-resolution appears to consistently outperform naïve interpolation and may improve image quality without biasing quantitative biomarkers.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:768-779.
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March 2020

Super-resolution musculoskeletal MRI using deep learning.

Magn Reson Med 2018 11 26;80(5):2139-2154. Epub 2018 Mar 26.

Department of Radiology, Stanford University, Stanford, California.

Purpose: To develop a super-resolution technique using convolutional neural networks for generating thin-slice knee MR images from thicker input slices, and compare this method with alternative through-plane interpolation methods.

Methods: We implemented a 3D convolutional neural network entitled DeepResolve to learn residual-based transformations between high-resolution thin-slice images and lower-resolution thick-slice images at the same center locations. DeepResolve was trained using 124 double echo in steady-state (DESS) data sets with 0.7-mm slice thickness and tested on 17 patients. Ground-truth images were compared with DeepResolve, clinically used tricubic interpolation, and Fourier interpolation methods, along with state-of-the-art single-image sparse-coding super-resolution. Comparisons were performed using structural similarity, peak SNR, and RMS error image quality metrics for a multitude of thin-slice downsampling factors. Two musculoskeletal radiologists ranked the 3 data sets and reviewed the diagnostic quality of the DeepResolve, tricubic interpolation, and ground-truth images for sharpness, contrast, artifacts, SNR, and overall diagnostic quality. Mann-Whitney U tests evaluated differences among the quantitative image metrics, reader scores, and rankings. Cohen's Kappa (κ) evaluated interreader reliability.

Results: DeepResolve had significantly better structural similarity, peak SNR, and RMS error than tricubic interpolation, Fourier interpolation, and sparse-coding super-resolution for all downsampling factors (p < .05, except 4 × and 8 × sparse-coding super-resolution downsampling factors). In the reader study, DeepResolve significantly outperformed (p < .01) tricubic interpolation in all image quality categories and overall image ranking. Both readers had substantial scoring agreement (κ = 0.73).

Conclusion: DeepResolve was capable of resolving high-resolution thin-slice knee MRI from lower-resolution thicker slices, achieving superior quantitative and qualitative diagnostic performance to both conventionally used and state-of-the-art methods.
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November 2018

Comparison of fMRI analysis methods for heterogeneous BOLD responses in block design studies.

Neuroimage 2017 02 16;147:390-408. Epub 2016 Dec 16.

Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA 94305, USA.

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.
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February 2017

Optogenetic Functional MRI.

J Vis Exp 2016 04 19(110). Epub 2016 Apr 19.

Neurology and Neurological Sciences, Stanford University; Electrical Engineering, Neurology and Neurological Sciences, Stanford University;

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.
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April 2016

Combining optogenetic stimulation and fMRI to validate a multivariate dynamical systems model for estimating causal brain interactions.

Neuroimage 2016 05 2;132:398-405. Epub 2016 Mar 2.

Stanford University School of Medicine, Stanford, USA. Electronic address:

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.
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May 2016

Frequency-selective control of cortical and subcortical networks by central thalamus.

Elife 2015 Dec 10;4:e09215. Epub 2015 Dec 10.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, United States.

Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation.
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December 2015

High spatial resolution compressed sensing (HSPARSE) functional MRI.

Magn Reson Med 2016 08 29;76(2):440-55. Epub 2015 Oct 29.

Department of Electrical Engineering, Stanford University, Stanford, California, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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August 2016

Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

Neuroimage 2015 Feb 22;107:229-241. Epub 2014 Oct 22.

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford, CA 94305, USA. Electronic address:

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.
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February 2015

High-throughput optogenetic functional magnetic resonance imaging with parallel computations.

J Neurosci Methods 2013 Sep 4;218(2):184-95. Epub 2013 Jun 4.

Department of Electrical Engineering, Stanford University, CA 94305, USA.

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.
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September 2013