Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tiss... more Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect.Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to ...
Submissions to the open international ISMRM 2015 tractography challenge. 20 research groups with ... more Submissions to the open international ISMRM 2015 tractography challenge. 20 research groups with extensive expertise in diffusion imaging from 12 countries participated in the competition and submitted a total of 96 tractograms generated using a large variety of tractography pipelines with different pre-processing, local reconstruction, tractography and post-processing algorithms. Each file represents an individual submission. The mapping from file name to team can be inferred from the listing in the paper, as seen in the references.
Cortical surface-based mapping has been widely used to compensate for the individual variability ... more Cortical surface-based mapping has been widely used to compensate for the individual variability of cortical shape and topology in anatomical and functional studies. While several surface mapping methods were proposed using different features or similarity metrics, a few studies have extensively and quantitatively evaluated different surface mapping methods. In this study we compared three algorithms for mapping surfaces, including multi-manifold large deformation diffeomorphic metric mapping (MM-
Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in th... more Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in the trigeminal nerve, however imaging has primarily focused on the peripheral nerve segment due to previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography (SAGIT) to study 36 TN subjects (right sided pain) and 36 sex matched controls, to examine the trigeminal nerve (CN V), pontine decussation (TPT), and thalamocortical fibers (S1). GP classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA (GFA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) metrics were evaluated for both groups, analyzing TN vs. control groups and affected vs. unaffected sides. Classifiers that performed at greater-or-equal-to 70% accuracy were included. GP classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 RD classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls, as well as abnormalities between affected and unaffected sides.
1.The registration or alignment of diffusion weighted images (DWI) with other imaging modalities ... more 1.The registration or alignment of diffusion weighted images (DWI) with other imaging modalities is a critical step in neuroimaging analysis. Within-subject T1-DWI co-registration is particularly instrumental. DWI-derived scalar images are commonly used as intermediates for T1-DWI co-registration, and the resulting registration transforms are applied to all other scalar images for analysis. The ideal registration intermediate should register well to T1 and other multimodal images and be practically easy to obtain. It is however, currently unclear which DWI-derived scalar image serves as the best intermediate. We aim to determine the best, practical, intermediate for image co-registration. T1 and DWI images were acquired from 20 healthy subjects. DWIs were acquired with 60 directions. Six DWI-derived scalar images were compared including: 1) fractional anisotropy (FA); 2) generalized FA (GFA); 3) B0 images; 4) mean DWIs with the B0 image (MDWI); 5) anisotropic power (AP) images. AP s...
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
OBJECTIVETractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a n... more OBJECTIVETractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a novel method conferring patient-specific selection of VIM coordinates for tremor surgery; however, its accuracy and clinical utility in magnetic resonance imaging–guided focused ultrasound (MRgFUS) thalamotomy compared to conventional indirect targeting has not been specifically addressed. This retrospective study sought to compare the treatment locations and potential adverse effect profiles of T-VIM with indirect targeting in a large cohort of MRgFUS thalamotomy patients.METHODST-VIM was performed using diffusion tractography outlining the pyramidal and medial lemniscus tracts in 43 MRgFUS thalamotomy patients. T-VIM coordinates were compared with the indirect treatment coordinates used in the procedure. Thalamotomy lesions were delineated on postoperative T1-weighted images and displaced (“translated”) by the anteroposterior and mediolateral difference between T-VIM and treatment coord...
Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasi... more Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemnisc...
Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interes... more Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interest in the neuroimaging of pain has highlighted changes in the root entry zone in TN, but also group level CNS grey and white matter abnormalities. Group differences in neuroimaging data are frequently evaluated with univariate statistics, however this approach is limited because it is based on single, or clusters of, voxels. In contrast, multivariate pattern analyses consider all the model's neuroanatomical features to capture a specific distributed spatial pattern. This approach has potential use as a prediction tool at the individual level. We hypothesized that a multivariate pattern classification method can distinguish specific patterns of abnormal white matter connectivity of classic TN from healthy controls (HC). Diffusion-weighted scans in 23 right-sided TN and matched controls were processed to extract whole brain inter-regional streamlines. We used a linear support vector mac...
Tractography based on non-invasive diffusion imaging is central to the study of human brain conne... more Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating ...
Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to... more Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to surgery. A proportion of patients, however, do not benefit and suffer ongoing pain. There are currently no imaging tools that permit the prediction of treatment response. To address this paucity, we used diffusion tensor imaging (DTI) to determine whether pre-surgical trigeminal nerve microstructural diffusivities can prognosticate response to TN treatment. In 31 TN patients and 16 healthy controls, multi-tensor tractography was used to extract DTI-derived metrics-axial (AD), radial (RD), mean diffusivity (MD), and fractional anisotropy (FA)-from the cisternal segment, root entry zone and pontine segment of trigeminal nerves for false discovery rate-corrected Student's t-tests. Ipsilateral diffusivities were bootstrap resampled to visualize group-level diffusivity thresholds of long-term response. To obtain an individual-level statistical classifier of surgical response, we conducte...
Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key play... more Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to...
Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studie... more Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.
Functional reorganization and structural damage occur in the brains of people with multiple scler... more Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting-state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting-state fMRI, T1-weighted and T2-weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease-related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor...
A structural or functional pattern of neuroplasticity that could systematically discriminate betw... more A structural or functional pattern of neuroplasticity that could systematically discriminate between people with impaired and preserved motor performance could help us to understand the brain networks contributing to preservation or compensation of behavior in multiple sclerosis (MS). This study aimed to (1) investigate whether a machine learning-based technique could accurately classify MS participants into groups defined by upper extremity function (i.e. motor function preserved (MP) vs. motor function impaired (MI)) based on their regional grey matter measures (GMM, cortical thickness and deep grey matter volume) and inter-regional functional connection (FC), (2) investigate which features (GMM, FC, or GMM + FC) could classify groups more accurately, and (3) identify the multivariate patterns of GMM and FCs that are most discriminative between MP and MI participants, and between each of these groups and the healthy controls (HCs). With 26 MP, 25 MI, and 21 HCs (age and sex matche...
Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tiss... more Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect.Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to ...
Submissions to the open international ISMRM 2015 tractography challenge. 20 research groups with ... more Submissions to the open international ISMRM 2015 tractography challenge. 20 research groups with extensive expertise in diffusion imaging from 12 countries participated in the competition and submitted a total of 96 tractograms generated using a large variety of tractography pipelines with different pre-processing, local reconstruction, tractography and post-processing algorithms. Each file represents an individual submission. The mapping from file name to team can be inferred from the listing in the paper, as seen in the references.
Cortical surface-based mapping has been widely used to compensate for the individual variability ... more Cortical surface-based mapping has been widely used to compensate for the individual variability of cortical shape and topology in anatomical and functional studies. While several surface mapping methods were proposed using different features or similarity metrics, a few studies have extensively and quantitatively evaluated different surface mapping methods. In this study we compared three algorithms for mapping surfaces, including multi-manifold large deformation diffeomorphic metric mapping (MM-
Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in th... more Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in the trigeminal nerve, however imaging has primarily focused on the peripheral nerve segment due to previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography (SAGIT) to study 36 TN subjects (right sided pain) and 36 sex matched controls, to examine the trigeminal nerve (CN V), pontine decussation (TPT), and thalamocortical fibers (S1). GP classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA (GFA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) metrics were evaluated for both groups, analyzing TN vs. control groups and affected vs. unaffected sides. Classifiers that performed at greater-or-equal-to 70% accuracy were included. GP classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 RD classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls, as well as abnormalities between affected and unaffected sides.
1.The registration or alignment of diffusion weighted images (DWI) with other imaging modalities ... more 1.The registration or alignment of diffusion weighted images (DWI) with other imaging modalities is a critical step in neuroimaging analysis. Within-subject T1-DWI co-registration is particularly instrumental. DWI-derived scalar images are commonly used as intermediates for T1-DWI co-registration, and the resulting registration transforms are applied to all other scalar images for analysis. The ideal registration intermediate should register well to T1 and other multimodal images and be practically easy to obtain. It is however, currently unclear which DWI-derived scalar image serves as the best intermediate. We aim to determine the best, practical, intermediate for image co-registration. T1 and DWI images were acquired from 20 healthy subjects. DWIs were acquired with 60 directions. Six DWI-derived scalar images were compared including: 1) fractional anisotropy (FA); 2) generalized FA (GFA); 3) B0 images; 4) mean DWIs with the B0 image (MDWI); 5) anisotropic power (AP) images. AP s...
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
OBJECTIVETractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a n... more OBJECTIVETractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a novel method conferring patient-specific selection of VIM coordinates for tremor surgery; however, its accuracy and clinical utility in magnetic resonance imaging–guided focused ultrasound (MRgFUS) thalamotomy compared to conventional indirect targeting has not been specifically addressed. This retrospective study sought to compare the treatment locations and potential adverse effect profiles of T-VIM with indirect targeting in a large cohort of MRgFUS thalamotomy patients.METHODST-VIM was performed using diffusion tractography outlining the pyramidal and medial lemniscus tracts in 43 MRgFUS thalamotomy patients. T-VIM coordinates were compared with the indirect treatment coordinates used in the procedure. Thalamotomy lesions were delineated on postoperative T1-weighted images and displaced (“translated”) by the anteroposterior and mediolateral difference between T-VIM and treatment coord...
Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasi... more Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemnisc...
Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interes... more Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interest in the neuroimaging of pain has highlighted changes in the root entry zone in TN, but also group level CNS grey and white matter abnormalities. Group differences in neuroimaging data are frequently evaluated with univariate statistics, however this approach is limited because it is based on single, or clusters of, voxels. In contrast, multivariate pattern analyses consider all the model's neuroanatomical features to capture a specific distributed spatial pattern. This approach has potential use as a prediction tool at the individual level. We hypothesized that a multivariate pattern classification method can distinguish specific patterns of abnormal white matter connectivity of classic TN from healthy controls (HC). Diffusion-weighted scans in 23 right-sided TN and matched controls were processed to extract whole brain inter-regional streamlines. We used a linear support vector mac...
Tractography based on non-invasive diffusion imaging is central to the study of human brain conne... more Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating ...
Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to... more Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to surgery. A proportion of patients, however, do not benefit and suffer ongoing pain. There are currently no imaging tools that permit the prediction of treatment response. To address this paucity, we used diffusion tensor imaging (DTI) to determine whether pre-surgical trigeminal nerve microstructural diffusivities can prognosticate response to TN treatment. In 31 TN patients and 16 healthy controls, multi-tensor tractography was used to extract DTI-derived metrics-axial (AD), radial (RD), mean diffusivity (MD), and fractional anisotropy (FA)-from the cisternal segment, root entry zone and pontine segment of trigeminal nerves for false discovery rate-corrected Student's t-tests. Ipsilateral diffusivities were bootstrap resampled to visualize group-level diffusivity thresholds of long-term response. To obtain an individual-level statistical classifier of surgical response, we conducte...
Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key play... more Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to...
Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studie... more Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.
Functional reorganization and structural damage occur in the brains of people with multiple scler... more Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting-state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting-state fMRI, T1-weighted and T2-weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease-related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor...
A structural or functional pattern of neuroplasticity that could systematically discriminate betw... more A structural or functional pattern of neuroplasticity that could systematically discriminate between people with impaired and preserved motor performance could help us to understand the brain networks contributing to preservation or compensation of behavior in multiple sclerosis (MS). This study aimed to (1) investigate whether a machine learning-based technique could accurately classify MS participants into groups defined by upper extremity function (i.e. motor function preserved (MP) vs. motor function impaired (MI)) based on their regional grey matter measures (GMM, cortical thickness and deep grey matter volume) and inter-regional functional connection (FC), (2) investigate which features (GMM, FC, or GMM + FC) could classify groups more accurately, and (3) identify the multivariate patterns of GMM and FCs that are most discriminative between MP and MI participants, and between each of these groups and the healthy controls (HCs). With 26 MP, 25 MI, and 21 HCs (age and sex matche...
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