Kevin Chuen Wing Chan

All Publications

• Functional genomics of primary congenital glaucoma by pathway analysis and functional characterization of CYP1B1 mutations. Vision research Faiq, M. A., Singh, H. N., Ali, M., Dada, R., Chan, K. C., Dada, T., Saluja, D. 2025; 227: 108534

  Abstract

  CYP1B1 is the most common gene implicated in primary congenital glaucoma (PCG) - the most common form of childhood glaucoma. How CYP1B1 mutations cause PCG is not known. Understanding the mechanism of PCG caused by CYP1B1 mutations is crucial for disease management, therapeutics development, and potential prevention. We performed a comprehensive metabolome/reactome analysis of CYP1B1 to enlist CYP1B1-mediated processes in eye development. The identified metabolic events were classified into major pathways. Functional analysis of these metabolic pathways was performed after cloning the CYP1B1 wild-type gene and expressing the wild-type and selected novel mutants (previously reported by our group L24R, F190L, H279D, and G329D) in heterologous hosts. Stability and enzymatic functions were investigated. Structural modeling of the wild-type and the variants was also performed. Reactome analysis revealed a total of 166 metabolic processes which could be classified into four major pathways including estradiol metabolism, retinoic acid metabolism, arachidonic acid metabolism, and melatonin metabolism. Stability assay revealed rapid denaturing of mutant proteins compared to wild-type. Enzymatic assays showed functional deficit in mutant proteins in metabolizing estradiol, retinoids, arachidonate, and melatonin. Modeling revealed that the examined mutations induced structural changes likely causative in functional loss in CYB1B1 as observed in enzymatic assays. Hence, mutations in the CYP1B1 gene are associated with a functional deficit in critical pathways of eye development. These findings implicate the potential contributions of altered metabolic regulations of estradiol, retinoids, arachidonate and melatonin to the pathogenesis of PCG during the processes of the formation of ocular structures and function.

  View details for DOI 10.1016/j.visres.2024.108534

  View details for PubMedID 39721180

• Stimulus-driven cerebrospinal fluid dynamics is impaired in glaucoma patients. bioRxiv : the preprint server for biology Bang, J. W., Parra, C., Yu, K., Lee, H. S., Wollstein, G., Schuman, J. S., Chan, K. C. 2025

  Abstract

  Cerebrospinal fluid (CSF) dynamics, driven by sensory stimulation-induced neuronal activity, is crucial for maintaining homeostasis and clearing metabolic waste. However, it remains unclear whether such CSF flow is impaired in age-related neurodegenerative diseases of the visual system. This study addresses this gap by examining CSF flow during visual stimulation in glaucoma patients and healthy older adults using functional magnetic resonance imaging. The findings reveal that in glaucoma, CSF inflow becomes decoupled from visually evoked blood-oxygenation-level-dependent (BOLD) response. Furthermore, stimulus-locked CSF patterns, characterized by decreases following stimulus onset and increases after offset, diminish as glaucoma severity worsens. Mediation analysis suggests that this flattened CSF pattern is driven by a flatter BOLD slope, resulting in a shallower CSF trough and a reduced rebound. These findings unveil a novel pathophysiological mechanism underlying disrupted stimulation-driven CSF dynamics in glaucoma and highlight potential in vivo biomarkers for monitoring CSF in the glaucomatous brain.

  View details for DOI 10.1101/2025.01.15.633258

  View details for PubMedID 39868211

  View details for PubMedCentralID PMC11761100

• Imaging methods for monitoring optic nerve regeneration Proteomics, Multi-Omics and Systems Biology in Optic Nerve Regeneration Yu, K., Kasi, A., James, R., Xue, Y., Chan, K. C. 2025: 15-35

  View details for DOI 10.1016/B978-0-443-15580-2.00002-3

• Age-related effects of optineurin deficiency in the mouse eye. Vision research Su, C. C., Liu, C., Adi, V., Chan, K. C., Tseng, H. C. 2024; 224: 108463

  Abstract

  Optineurin (OPTN) is a gene associated with familial normal tension glaucoma (NTG). While NTG involves intraocular pressure (IOP)-independent neurodegeneration of the visual pathway that progresses with age, how OPTN dysfunction leads to NTG remains unclear. Here, we generated an OPTN knockout mouse (Optn-/-) model to test the hypothesis that a loss-of-function mechanism induces structural and functional eye deterioration with aging. Eye anatomy, visual function, IOP, retinal histology, and retinal ganglion cell survival were compared to littermate wild-type (WT) control mice. Consistent with OPTN's role in NTG, loss of OPTN did not increase IOP or alter gross eye anatomy in young (2-3 months) or aged (12 months) mice. When retinal layers were quantitated, young Optn-/- mice had thinner retina in the peripheral regions than young WT mice, primarily due to thinner ganglion cell-inner plexiform layers. Despite this, visual function in Optn-/- mice was not severely impaired, even with aging. We also assessed relative abundance of retinal cell subtypes, including amacrine cells, bipolar cells, cone photoreceptors, microglia, and astrocytes. While many of these cellular subtypes were unaffected by Optn deletion, more dopaminergic amacrine cells were observed in aged Optn-/- mice. Taken together, our findings showed that complete loss of Optn resulted in mild retinal changes and less visual function impairment, supporting the possibility that OPTN-associated glaucoma does not result from a loss-of-function disease mechanism. Further research using these Optn mice will elucidate detailed molecular pathways involved in NTG and identify clinical or environmental risk factors that can be targeted for glaucoma treatment.

  View details for DOI 10.1016/j.visres.2024.108463

  View details for PubMedID 39208752

• NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis improves brain activity detection across rodent and human functional MRI contexts. Imaging neuroscience (Cambridge, Mass.) Chan, R. W., Hamilton-Fletcher, G., Edelman, B. J., Faiq, M. A., Sajitha, T. A., Moeller, S., Chan, K. C. 2024; 2: 1-18

  Abstract

  NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis (PCA) has been shown to selectively suppress thermal noise and improve the temporal signal-to-noise ratio (tSNR) in human functional magnetic resonance imaging (fMRI). However, the feasibility to improve data quality for rodent fMRI using NORDIC PCA remains uncertain. NORDIC PCA may also be particularly beneficial for improving topological brain mapping, as conventional mapping requires precise spatiotemporal signals from large datasets (ideally ~1 hour acquisition) for individual representations. In this study, we evaluated the effects of NORDIC PCA compared with "Standard" processing in various rodent fMRI contexts that range from task-evoked optogenetic fMRI to resting-state fMRI. We also evaluated the effects of NORDIC PCA on human resting-state and retinotopic mapping fMRI via population receptive field (pRF) modeling. In rodent optogenetic fMRI, apart from doubling the tSNR, NORDIC PCA resulted in a larger number of activated voxels and a significant decrease in the variance of evoked brain responses without altering brain morphology. In rodent resting-state fMRI, we found that NORDIC PCA induced a nearly threefold increase in tSNR and preserved task-free relative cerebrovascular reactivity (rCVR) across cortical depth. NORDIC PCA further improved the detection of TGN020-induced aquaporin-4 inhibition on rCVR compared with Standard processing without NORDIC PCA. NORDIC PCA also increased the tSNR for both human resting-state and pRF fMRI, and for the latter also increased activation cluster sizes while retaining retinotopic organization. This suggests that NORDIC PCA preserves the spatiotemporal precision of fMRI signals needed for pRF analysis, and effectively captures small activity changes with high sensitivity. Taken together, these results broadly demonstrate the value of NORDIC PCA for the enhanced detection of neural dynamics across various rodent and human fMRI contexts. This can in turn play an important role in improving fMRI image quality and sensitivity for translational and preclinical neuroimaging research.

  View details for DOI 10.1162/imag_a_00325

  View details for PubMedID 39463889

  View details for PubMedCentralID PMC11506209

• Contributions of Brain Microstructures and Metabolism to Visual Field Loss Patterns in Glaucoma Using Archetypal and Information Gain Analyses. Investigative ophthalmology & visual science Pang, Y., Bang, J. W., Kasi, A., Li, J., Parra, C., Fieremans, E., Wollstein, G., Schuman, J. S., Wang, M., Chan, K. C. 2024; 65 (8): 15

  Abstract

  To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures.Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma.In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma.Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.

  View details for DOI 10.1167/iovs.65.8.15

  View details for PubMedID 38975942

  View details for PubMedCentralID PMC11232899

• Using Transfer Learning to Refine Object Detection Models for Blind and Low Vision Users. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Bhandari, A., Batutis, G. S., Jain, A., Sico, M. C., Hamilton-Fletcher, G., Feng, C., Hudson, T. E., Rizzo, J. R., Chan, K. C. 2024; 2024: 1-4

  Abstract

  Object detection models available on smartphones such as YOLOv8 can potentially help identify and locate objects of interest to people who are blind or low vision (pBLV). However, current models may miss crucial objects for pBLV. Here, we compared 5 transfer learning methods for adding new classes of interest to pBLV navigation that are absent from the Common Objects in Context (COCO) training dataset. Using a rebalanced COCO dataset with these new classes, we revised public YOLOv8s models via the following methods: revising all pretrained weights; freezing 22, 21 or 15 layers; and few-shot learning. These approaches achieved overall mean average precision (mAP-50) from 0.342 (20 min training time; few-shot learning) to 0.420 (9.2 hrs; revising all pretrained weights). Among the frozen layer models, the 15 frozen layer model had the best mAP-50 performance of 0.419 (7.7 hrs); hyperparameter tuning on this model increased mAP-50 to 0.423. When applied to a larger YOLOv8xl model, mAP-50 reached 0.511 after 50 epochs. Our results highlight how object detection models can be adapted for the benefit of pBLV users even when developers have limited training data or computational resources.

  View details for DOI 10.1109/EMBC53108.2024.10782343

  View details for PubMedID 40039335

• Early inner plexiform layer thinning and retinal nerve fiber layer thickening in excitotoxic retinal injury using deep learning-assisted optical coherence tomography. Acta neuropathologica communications Ma, D., Deng, W., Khera, Z., Sajitha, T. A., Wang, X., Wollstein, G., Schuman, J. S., Lee, S., Shi, H., Ju, M. J., Matsubara, J., Beg, M. F., Sarunic, M., Sappington, R. M., Chan, K. C. 2024; 12 (1): 19

  Abstract

  Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation. Before and after unilateral intravitreal NMDA injection in nine adult Long Evans rats, spectral-domain optical coherence tomography (OCT) was used to acquire volumetric retinal images in both eyes over 4 weeks. Ten retinal layers were automatically segmented from the OCT data using our deep learning-based algorithm. Retinal degeneration was evaluated using layer-specific retinal thickness changes at each time point (before, and at 3, 7, and 28 days after NMDA injection). Within the inner retina, our OCT results showed that retinal thinning occurred first in the inner plexiform layer at 3 days after NMDA injection, followed by the inner nuclear layer at 7 days post-injury. In contrast, the retinal nerve fiber layer exhibited an initial thickening 3 days after NMDA injection, followed by normalization and thinning up to 4 weeks post-injury. Our results demonstrated the pathological cascades of NMDA-induced neurotoxicity across different layers of the retina. The early inner plexiform layer thinning suggests early dendritic shrinkage, whereas the initial retinal nerve fiber layer thickening before subsequent normalization and thinning indicates early inflammation before axonal loss and cell death. These findings implicate the inner plexiform layer as an early imaging biomarker of excitotoxic retinal degeneration, whereas caution is warranted when interpreting the ganglion cell complex combining retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses in conventional OCT measures. Deep learning-assisted retinal layer segmentation and longitudinal OCT monitoring can help evaluate the different phases of retinal layer damage upon excitotoxicity.

  View details for DOI 10.1186/s40478-024-01732-z

  View details for PubMedID 38303097

  View details for PubMedCentralID PMC10835918

• Accuracy and Usability of Smartphone-Based Distance Estimation Approaches for Visual Assistive Technology Development. IEEE open journal of engineering in medicine and biology Hamilton-Fletcher, G., Liu, M., Sheng, D., Feng, C., Hudson, T. E., Rizzo, J. R., Chan, K. C. 2024; 5: 54-58

  Abstract

  Goal: Distance information is highly requested in assistive smartphone Apps by people who are blind or low vision (PBLV). However, current techniques have not been evaluated systematically for accuracy and usability. Methods: We tested five smartphone-based distance-estimation approaches in the image center and periphery at 1-3 meters, including machine learning (CoreML), infrared grid distortion (IR_self), light detection and ranging (LiDAR_back), and augmented reality room-tracking on the front (ARKit_self) and back-facing cameras (ARKit_back). Results: For accuracy in the image center, all approaches had <±2.5 cm average error, except CoreML which had ±5.2-6.2 cm average error at 2-3 meters. In the periphery, all approaches were more inaccurate, with CoreML and IR_self having the highest average errors at ±41 cm and ±32 cm respectively. For usability, CoreML fared favorably with the lowest central processing unit usage, second lowest battery usage, highest field-of-view, and no specialized sensor requirements. Conclusions: We provide key information that helps design reliable smartphone-based visual assistive technologies to enhance the functionality of PBLV.

  View details for DOI 10.1109/OJEMB.2024.3358562

  View details for PubMedID 38487094

  View details for PubMedCentralID PMC10939328

• Editorial: Translational opportunities for AI in glaucoma. Frontiers in ophthalmology Chan, K. C., Sappington, R. M. 2023; 3: 1299582

  View details for DOI 10.3389/fopht.2023.1299582

  View details for PubMedID 38983047

  View details for PubMedCentralID PMC11182079

• Improved reconstruction of crossing fibers in the mouse optic pathways with orientation distribution function fingerprinting. Magnetic resonance in medicine Filipiak, P., Sajitha, T. A., Shepherd, T. M., Clarke, K., Goldman, H., Placantonakis, D. G., Zhang, J., Chan, K. C., Boada, F. E., Baete, S. H. 2023

  Abstract

  PURPOSE: The accuracy of diffusion MRI tractography reconstruction decreases in the white matter regions with crossing fibers. The optic pathways in rodents provide a challenging structure to test new diffusion tractography approaches because of the small crossing volume within the optic chiasm and the unbalanced 9:1 proportion between the contra- and ipsilateral neural projections from the retina to the lateral geniculate nucleus, respectively.METHODS: Common approaches based on Orientation Distribution Function (ODF) peak finding or statistical inference were compared qualitatively and quantitatively to ODF Fingerprinting (ODF-FP) for reconstruction of crossing fibers within the optic chiasm using in vivo diffusion MRI ( n = 18 $$ n=18 $$ healthy C57BL/6 mice). Manganese-Enhanced MRI (MEMRI) was obtained after intravitreal injection of manganese chloride and used as a reference standard for the optic pathway anatomy.RESULTS: ODF-FP outperformed by over 100% all the tested methods in terms of the ratios between the contra- and ipsilateral segments of the reconstructed optic pathways as well as the spatial overlap between tractography and MEMRI.CONCLUSION: In this challenging model system, ODF-Fingerprinting reduced uncertainty of diffusion tractography for complex structural formations of fiber bundles.

  View details for DOI 10.1002/mrm.29911

  View details for PubMedID 37927121

• Training AI to Recognize Objects of Interest to the Blind and Low Vision Community. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Sankarnarayanan, T., Paciorkowski, L., Parikh, K., Hamilton-Fletcher, G., Feng, C., Sheng, D., Hudson, T. E., Rizzo, J. R., Chan, K. C. 2023; 2023: 1-4

  Abstract

  Recent object detection models show promising advances in their architecture and performance, expanding potential applications for the benefit of persons with blindness or low vision (pBLV). However, object detection models are usually trained on generic data rather than datasets that focus on the needs of pBLV. Hence, for applications that locate objects of interest to pBLV, object detection models need to be trained specifically for this purpose. Informed by prior interviews, questionnaires, and Microsoft's ORBIT research, we identified thirty-five objects pertinent to pBLV. We employed this user-centric feedback to gather images of these objects from the Google Open Images V6 dataset. We subsequently trained a YOLOv5x model with this dataset to recognize these objects of interest. We demonstrate that the model can identify objects that previous generic models could not, such as those related to tasks of daily functioning - e.g., coffee mug, knife, fork, and glass. Crucially, we show that careful pruning of a dataset with severe class imbalances leads to a rapid, noticeable improvement in the overall performance of the model by two-fold, as measured using the mean average precision at the intersection over union thresholds from 0.5 to 0.95 (mAP50-95). Specifically, mAP50-95 improved from 0.14 to 0.36 on the seven least prevalent classes in the training dataset. Overall, we show that careful curation of training data can improve training speed and object detection outcomes. We show clear directions on effectively customizing training data to create models that focus on the desires and needs of pBLV.Clinical Relevance- This work demonstrated the benefits of developing assistive AI technology customized to individual users or the wider BLV community.

  View details for DOI 10.1109/EMBC40787.2023.10340454

  View details for PubMedID 38082714

• GABA decrease is associated with degraded neural specificity in the visual cortex of glaucoma patients. Communications biology Bang, J. W., Parra, C., Yu, K., Wollstein, G., Schuman, J. S., Chan, K. C. 2023; 6 (1): 679

  Abstract

  Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study shows that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, our study shows that the reduction of GABA but not glutamate predicts the neural specificity. This association is independent of the impairments on the retina structure, age, and the gray matter volume of the visual cortex. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma.

  View details for DOI 10.1038/s42003-023-04918-8

  View details for PubMedID 37386293

  View details for PubMedCentralID PMC10310759

• Ocular manifestations of central insulin resistance. Neural regeneration research Faiq, M. A., Sengupta, T., Nath, M., Velpandian, T., Saluja, D., Dada, R., Dada, T., Chan, K. C. 2023; 18 (5): 1139-1146

  Abstract

  Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

  View details for DOI 10.4103/1673-5374.355765

  View details for PubMedID 36255004

  View details for PubMedCentralID PMC9827783

• Diverging patterns of plasticity in the nucleus basalis of Meynert in early- and late-onset blindness. Brain communications Bang, J. W., Chan, R. W., Parra, C., Murphy, M. C., Schuman, J. S., Nau, A. C., Chan, K. C. 2023; 5 (2): fcad119

  Abstract

  Plasticity in the brain is impacted by an individual's age at the onset of the blindness. However, what drives the varying degrees of plasticity remains largely unclear. One possible explanation attributes the mechanisms for the differing levels of plasticity to the cholinergic signals originating in the nucleus basalis of Meynert. This explanation is based on the fact that the nucleus basalis of Meynert can modulate cortical processes such as plasticity and sensory encoding through its widespread cholinergic projections. Nevertheless, there is no direct evidence indicating that the nucleus basalis of Meynert undergoes plastic changes following blindness. Therefore, using multiparametric magnetic resonance imaging, we examined if the structural and functional properties of the nucleus basalis of Meynert differ between early blind, late blind and sighted individuals. We observed that early and late blind individuals had a preserved volumetric size and cerebrovascular reactivity in the nucleus basalis of Meynert. However, we observed a reduction in the directionality of water diffusion in both early and late blind individuals compared to sighted individuals. Notably, the nucleus basalis of Meynert presented diverging patterns of functional connectivity between early and late blind individuals. This functional connectivity was enhanced at both global and local (visual, language and default-mode networks) levels in the early blind individuals, but there were little-to-no changes in the late blind individuals when compared to sighted controls. Furthermore, the age at onset of blindness predicted both global and local functional connectivity. These results suggest that upon reduced directionality of water diffusion in the nucleus basalis of Meynert, cholinergic influence may be stronger for the early blind compared to the late blind individuals. Our findings are important to unravelling why early blind individuals present stronger and more widespread cross-modal plasticity compared to late blind individuals.

  View details for DOI 10.1093/braincomms/fcad119

  View details for PubMedID 37101831

  View details for PubMedCentralID PMC10123399

• Visual Plasticity in Adulthood: Perspectives from Hebbian and Homeostatic Plasticity. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry Bang, J. W., Hamilton-Fletcher, G., Chan, K. C. 2023; 29 (1): 117-138

  Abstract

  The visual system retains profound plastic potential in adulthood. In the current review, we summarize the evidence of preserved plasticity in the adult visual system during visual perceptual learning as well as both monocular and binocular visual deprivation. In each condition, we discuss how such evidence reflects two major cellular mechanisms of plasticity: Hebbian and homeostatic processes. We focus on how these two mechanisms work together to shape plasticity in the visual system. In addition, we discuss how these two mechanisms could be further revealed in future studies investigating cross-modal plasticity in the visual system.

  View details for DOI 10.1177/10738584211037619

  View details for PubMedID 34382456

  View details for PubMedCentralID PMC9356772

• Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications. Frontiers in ophthalmology Ma, D., Pasquale, L. R., Girard, M. J., Leung, C. K., Jia, Y., Sarunic, M. V., Sappington, R. M., Chan, K. C. 2023; 2

  Abstract

  Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data.

  View details for DOI 10.3389/fopht.2022.1057896

  View details for PubMedID 36866233

  View details for PubMedCentralID PMC9976697

• Glymphatic imaging and modulation of the optic nerve. Neural regeneration research Kasi, A., Liu, C., Faiq, M. A., Chan, K. C. 2022; 17 (5): 937-947

  Abstract

  Optic nerve health is essential for proper function of the visual system. However, the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve, such as glaucoma, is not fully understood. Recently, it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases. The ability to clear metabolic waste is essential for tissue homeostasis in mammals, including humans. While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions, there is growing evidence of a glymphatic system in the central nervous system, which structurally includes the optic nerve. Named to acknowledge the supportive role of astroglial cells, this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system. Herein, we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve. We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents, aquaporin 4-null rodents, and humans; glymphatic imaging studies in diseases where the optic nerve is impaired; and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health. We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.

  View details for DOI 10.4103/1673-5374.324829

  View details for PubMedID 34558505

  View details for PubMedCentralID PMC8552868

• In vivo MRI evaluation of anterograde manganese transport along the visual pathway following whole eye transplantation. Journal of neuroscience methods Komatsu, C., van der Merwe, Y., He, L., Kasi, A., Sims, J. R., Miller, M. R., Rosner, I. A., Khatter, N. J., Su, A. A., Schuman, J. S., Washington, K. M., Chan, K. C. 2022; 372: 109534

  Abstract

  Since adult mammalian retinal ganglion cells cannot regenerate after injury, we have recently established a whole-eye transplantation (WET) rat model that provides an intact optical system to investigate potential surgical restoration of irreversible vision loss. However, it remains to be elucidated whether physiological axoplasmic transport exists in the transplanted visual pathway.We developed an in vivo imaging model system to assess WET integration using manganese-enhanced magnetic resonance imaging (MEMRI) in rats. Since Mn2+ is a calcium analogue and an active T1-positive contrast agent, the levels of anterograde manganese transport can be evaluated in the visual pathways upon intravitreal Mn2+ administration into both native and transplanted eyes.No significant intraocular pressure difference was found between native and transplanted eyes, whereas comparable manganese enhancement was observed between native and transplanted intraorbital optic nerves, suggesting the presence of anterograde manganese transport after WET. No enhancement was detected across the coaptation site in the higher visual areas of the recipient brain.Existing imaging methods to assess WET focus on either the eye or local optic nerve segments without direct visualization and longitudinal quantification of physiological transport along the transplanted visual pathway, hence the development of in vivo MEMRI.Our established imaging platform indicated that essential physiological transport exists in the transplanted optic nerve after WET. As neuroregenerative approaches are being developed to connect the transplanted eye to the recipient's brain, in vivo MEMRI is well-suited to guide strategies for successful WET integration for vision restoration.

  View details for DOI 10.1016/j.jneumeth.2022.109534

  View details for PubMedID 35202613

  View details for PubMedCentralID PMC8940646

• Advanced Diffusion MRI of the Visual System in Glaucoma: From Experimental Animal Models to Humans. Biology Mendoza, M., Shotbolt, M., Faiq, M. A., Parra, C., Chan, K. C. 2022; 11 (3)

  Abstract

  Glaucoma is a group of ophthalmologic conditions characterized by progressive retinal ganglion cell death, optic nerve degeneration, and irreversible vision loss. While intraocular pressure is the only clinically modifiable risk factor, glaucoma may continue to progress at controlled intraocular pressure, indicating other major factors in contributing to the disease mechanisms. Recent studies demonstrated the feasibility of advanced diffusion magnetic resonance imaging (dMRI) in visualizing the microstructural integrity of the visual system, opening new possibilities for non-invasive characterization of glaucomatous brain changes for guiding earlier and targeted intervention besides intraocular pressure lowering. In this review, we discuss dMRI methods currently used in visual system investigations, focusing on the eye, optic nerve, optic tract, subcortical visual brain nuclei, optic radiations, and visual cortex. We evaluate how conventional diffusion tensor imaging, higher-order diffusion kurtosis imaging, and other extended dMRI techniques can assess the neuronal and glial integrity of the visual system in both humans and experimental animal models of glaucoma, among other optic neuropathies or neurodegenerative diseases. We also compare the pros and cons of these methods against other imaging modalities. A growing body of dMRI research indicates that this modality holds promise in characterizing early glaucomatous changes in the visual system, determining the disease severity, and identifying potential neurotherapeutic targets, offering more options to slow glaucoma progression and to reduce the prevalence of this world's leading cause of irreversible but preventable blindness.

  View details for DOI 10.3390/biology11030454

  View details for PubMedID 35336827

  View details for PubMedCentralID PMC8945790

• Role of Structural, Metabolic, and Functional MRI in Monitoring Visual System Impairment and Recovery. Journal of magnetic resonance imaging : JMRI Sims, J. R., Chen, A. M., Sun, Z., Deng, W., Colwell, N. A., Colbert, M. K., Zhu, J., Sainulabdeen, A., Faiq, M. A., Bang, J. W., Chan, K. C. 2021; 54 (6): 1706-1729

  Abstract

  The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft-tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system. LEVEL OF EVIDENCE 3:   TECHNICAL EFFICACY STAGE 3:  .

  View details for DOI 10.1002/jmri.27367

  View details for PubMedID 33009710

  View details for PubMedCentralID PMC8099039

• Sensory integration abilities for balance in glaucoma, a preliminary study. Scientific reports O'Connell, C., Redfern, M., Chan, K. C., Wollstein, G., Conner, I. P., Cham, R. 2021; 11 (1): 19691

  Abstract

  The goal of this study was to quantify the association between sensory integration abilities relevant for standing balance and disease stage in glaucoma. The disease stage was assessed using both functional (visual field deficit) and structural (retinal nerve fiber layer thickness) deficits in the better and worse eye. Balance was assessed using an adapted version of the well-established Sensory Organization Test (SOT). Eleven subjects diagnosed with mild to moderate glaucoma stood for 3 min in 6 sensory challenging postural conditions. Balance was assessed using sway magnitude and sway speed computed based on center-of-pressure data. Mixed linear regression analyses were used to investigate the associations between glaucoma severity and balance measures. Findings revealed that the visual field deficit severity in the better eye was associated with increased standing sway speed. This finding was confirmed in eyes open and closed conditions. Balance was not affected by the extent of the visual field deficit in the worse eye. Similarly, structural damage in either eye was not associated with the balance measures. In summary, this study found that postural control performance was associated with visual field deficit severity. The fact that this was found during eyes closed as well suggests that reduced postural control in glaucoma is not entirely attributed to impaired peripheral visual inputs. A larger study is needed to further investigate potential interactions between visual changes and central processing changes contributing to reduced balance function and increased incidence of falls in adults with glaucoma.

  View details for DOI 10.1038/s41598-021-98518-3

  View details for PubMedID 34608185

  View details for PubMedCentralID PMC8490466

• Oral Scutellarin Treatment Ameliorates Retinal Thinning and Visual Deficits in Experimental Glaucoma. Frontiers in medicine Zhu, J., Sainulabdeen, A., Akers, K., Adi, V., Sims, J. R., Yarsky, E., Yan, Y., Yu, Y., Ishikawa, H., Leung, C. K., Wollstein, G., Schuman, J. S., Wei, W., Chan, K. C. 2021; 8: 681169

  Abstract

  Purpose: Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that can exert neuroprotective effects in the eye and brain. Here, we investigated the neurobehavioral effects of scutellarin treatment in a chronic IOP elevation model. Methods: Ten adult C57BL/6J mice were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice received unilateral intracameral injection of phosphate-buffered saline only. Another eight mice with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin. Tonometry, optical coherence tomography, and optokinetics were performed longitudinally for 4 weeks to monitor the IOP, retinal nerve fiber layer thickness, total retinal thickness, visual acuity, and contrast sensitivity of both eyes in all three groups. Results: Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant inter-eye IOP difference between scutellarin treatment and untreated groups. Upon scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes. No significant difference in retinal thickness or optokinetic measures was found in the contralateral, non-treated eyes over time or between all groups. Conclusion: Using the non-invasive measuring platform, oral scutellarin treatment appeared to preserve retinal structure and visual function upon chronic IOP elevation in mice. Scutellarin may be a novel neurotherapeutic agent for glaucoma treatment.

  View details for DOI 10.3389/fmed.2021.681169

  View details for PubMedID 34414202

  View details for PubMedCentralID PMC8369066

• Diffusion Tensor Imaging of Visual Pathway Abnormalities in Five Glaucoma Animal Models. Investigative ophthalmology & visual science Colbert, M. K., Ho, L. C., van der Merwe, Y., Yang, X., McLellan, G. J., Hurley, S. A., Field, A. S., Yun, H., Du, Y., Conner, I. P., Parra, C., Faiq, M. A., Fingert, J. H., Wollstein, G., Schuman, J. S., Chan, K. C. 2021; 62 (10): 21

  Abstract

  To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI).Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract.Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls.Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.

  View details for DOI 10.1167/iovs.62.10.21

  View details for PubMedID 34410298

  View details for PubMedCentralID PMC8383913

• In vivo MRI evaluation of early postnatal development in normal and impaired rat eyes. Scientific reports Au, J. M., Kancherla, S., Hamade, M., Mendoza, M., Chan, K. C. 2021; 11 (1): 15513

  Abstract

  This study employed in vivo 7-T magnetic resonance imaging (MRI) to evaluate the postnatal ocular growth patterns under normal development or neonatal impairments in Sprague-Dawley rats. Using T2-weighted imaging on healthy rats from postnatal day (P) 1 (newborn) to P60 (adult), the volumes of the anterior chamber and posterior chamber (ACPC), lens, and vitreous humor increased logistically with ACPC expanding by 33-fold and the others by fivefold. Intravitreal potassium dichromate injection at P1, P7, and P14 led to T1-weighted signal enhancement in the developing retina by 188-289%. Upon unilateral hypoxic-ischemic encephalopathy at P7, monocular deprivation at P15, and monocular enucleation at P1, T2-weighted imaging of the adult rats showed decreased ocular volumes to different extents. In summary, in vivo high-field MRI allows for non-invasive evaluation of early postnatal development in the normal and impaired rat eyes. Chromium-enhanced MRI appeared effective in examining the developing retina before natural eyelid opening at P14 with relevance to lipid metabolism. The reduced ocular volumes upon neonatal visual impairments provided evidence to the emerging problems of why some impaired visual outcomes cannot be solely predicted by neurological assessments and suggested the need to look into both the eye and the brain under such conditions.

  View details for DOI 10.1038/s41598-021-93991-2

  View details for PubMedID 34330952

  View details for PubMedCentralID PMC8324881

• Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics van der Merwe, Y., Murphy, M. C., Sims, J. R., Faiq, M. A., Yang, X. L., Ho, L. C., Conner, I. P., Yu, Y., Leung, C. K., Wollstein, G., Schuman, J. S., Chan, K. C. 2021; 18 (2): 1339-1359

  Abstract

  Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.

  View details for DOI 10.1007/s13311-021-01033-6

  View details for PubMedID 33846961

  View details for PubMedCentralID PMC8423893

• Quantitative imaging of the clearance systems in the eye and the brain. Quantitative imaging in medicine and surgery Deng, W., Liu, C., Parra, C., Sims, J. R., Faiq, M. A., Sainulabdeen, A., Song, H., Chan, K. C. 2020; 10 (1): 1-14

  View details for DOI 10.21037/qims.2019.11.18

  View details for PubMedID 31956524

  View details for PubMedCentralID PMC6960420

• Author Correction: Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function. Scientific reports van der Merwe, Y., Faust, A. E., Sakalli, E. T., Westrick, C. C., Hussey, G., Chan, K. C., Conner, I. P., Fu, V. L., Badylak, S. F., Steketee, M. B. 2019; 9 (1): 15799

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41598-019-50829-2

  View details for PubMedID 31659169

  View details for PubMedCentralID PMC6817938

• Widespread brain reorganization perturbs visuomotor coordination in early glaucoma. Scientific reports Trivedi, V., Bang, J. W., Parra, C., Colbert, M. K., O'Connell, C., Arshad, A., Faiq, M. A., Conner, I. P., Redfern, M. S., Wollstein, G., Schuman, J. S., Cham, R., Chan, K. C. 2019; 9 (1): 14168

  Abstract

  Glaucoma is the world's leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls.

  View details for DOI 10.1038/s41598-019-50793-x

  View details for PubMedID 31578409

  View details for PubMedCentralID PMC6775162

• Cholinergic nervous system and glaucoma: From basic science to clinical applications. Progress in retinal and eye research Faiq, M. A., Wollstein, G., Schuman, J. S., Chan, K. C. 2019; 72: 100767

  Abstract

  The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.

  View details for DOI 10.1016/j.preteyeres.2019.06.003

  View details for PubMedID 31242454

  View details for PubMedCentralID PMC6739176

• Intracameral injection of a chemically cross-linked hydrogel to study chronic neurodegeneration in glaucoma. Acta biomaterialia Chan, K. C., Yu, Y., Ng, S. H., Mak, H. K., Yip, Y. W., van der Merwe, Y., Ren, T., Yung, J. S., Biswas, S., Cao, X., Chau, Y., Leung, C. K. 2019; 94: 219-231

  Abstract

  Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ± 3 and 24 ± 3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.

  View details for DOI 10.1016/j.actbio.2019.06.005

  View details for PubMedID 31176841

  View details for PubMedCentralID PMC6660904

• Applications of Manganese-Enhanced Magnetic Resonance Imaging in Ophthalmology and Visual Neuroscience. Frontiers in neural circuits Deng, W., Faiq, M. A., Liu, C., Adi, V., Chan, K. C. 2019; 13: 35

  Abstract

  Understanding the mechanisms of vision in health and disease requires knowledge of the anatomy and physiology of the eye and the neural pathways relevant to visual perception. As such, development of imaging techniques for the visual system is crucial for unveiling the neural basis of visual function or impairment. Magnetic resonance imaging (MRI) offers non-invasive probing of the structure and function of the neural circuits without depth limitation, and can help identify abnormalities in brain tissues in vivo. Among the advanced MRI techniques, manganese-enhanced MRI (MEMRI) involves the use of active manganese contrast agents that positively enhance brain tissue signals in T1-weighted imaging with respect to the levels of connectivity and activity. Depending on the routes of administration, accumulation of manganese ions in the eye and the visual pathways can be attributed to systemic distribution or their local transport across axons in an anterograde fashion, entering the neurons through voltage-gated calcium channels. The use of the paramagnetic manganese contrast in MRI has a wide range of applications in the visual system from imaging neurodevelopment to assessing and monitoring neurodegeneration, neuroplasticity, neuroprotection, and neuroregeneration. In this review, we present four major domains of scientific inquiry where MEMRI can be put to imperative use - deciphering neuroarchitecture, tracing neuronal tracts, detecting neuronal activity, and identifying or differentiating glial activity. We deliberate upon each category studies that have successfully employed MEMRI to examine the visual system, including the delivery protocols, spatiotemporal characteristics, and biophysical interpretation. Based on this literature, we have identified some critical challenges in the field in terms of toxicity, and sensitivity and specificity of manganese enhancement. We also discuss the pitfalls and alternatives of MEMRI which will provide new avenues to explore in the future.

  View details for DOI 10.3389/fncir.2019.00035

  View details for PubMedID 31156399

  View details for PubMedCentralID PMC6530364

• Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function. Scientific reports van der Merwe, Y., Faust, A. E., Sakalli, E. T., Westrick, C. C., Hussey, G., Chan, K. C., Conner, I. P., Fu, V. L., Badylak, S. F., Steketee, M. B. 2019; 9 (1): 3482

  Abstract

  Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information to the brain, often leads to RGC axon degeneration and permanently lost visual function. Herein this study shows matrix-bound nanovesicles (MBV), a distinct class of extracellular nanovesicle localized specifically to the extracellular matrix (ECM) of healthy tissues, can neuroprotect RGCs and preserve visual function after severe, intraocular pressure (IOP) induced ischemia in rat. Intravitreal MBV injections attenuated IOP-induced RGC axon degeneration and death, protected RGC axon connectivity to visual nuclei in the brain, and prevented loss in retinal function as shown by histology, anterograde axon tracing, manganese-enhanced magnetic resonance imaging, and electroretinography. In the optic nerve, MBV also prevented IOP-induced decreases in growth associated protein-43 and IOP-induced increases in glial fibrillary acidic protein. In vitro studies showed MBV suppressed pro-inflammatory signaling by activated microglia and astrocytes, stimulated RGC neurite growth, and neuroprotected RGCs from neurotoxic media conditioned by pro-inflammatory astrocytes. Thus, MBV can positively modulate distinct signaling pathways (e.g., inflammation, cell death, and axon growth) in diverse cell types. Since MBV are naturally derived, bioactive factors present in numerous FDA approved devices, MBV may be readily useful, not only experimentally, but also clinically as immunomodulatory, neuroprotective factors for treating trauma or disease in the retina as well as other CNS tissues.

  View details for DOI 10.1038/s41598-019-39861-4

  View details for PubMedID 30837658

  View details for PubMedCentralID PMC6400956

• In vivo imaging of structural, metabolic and functional brain changes in glaucoma. Neural regeneration research Kasi, A., Faiq, M. A., Chan, K. C. 2019; 14 (3): 446-449

  Abstract

  Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease.

  View details for DOI 10.4103/1673-5374.243712

  View details for PubMedID 30539811

  View details for PubMedCentralID PMC6334611

• Spatial Patterns and Age-Related Changes of the Collagen Crimp in the Human Cornea and Sclera. Investigative ophthalmology & visual science Gogola, A., Jan, N. J., Brazile, B., Lam, P., Lathrop, K. L., Chan, K. C., Sigal, I. A. 2018; 59 (7): 2987-2998

  Abstract

  Collagen is the main load-bearing component of the eye, and collagen crimp is a critical determinant of tissue mechanical behavior. We test the hypothesis that collagen crimp morphology varies over the human cornea and sclera and with age.We analyzed 42 axial whole-globe sections from 20 normal eyes of 20 human donors, ranging in age from 0.08 (1 month) to 97 years. The sections were imaged using polarized light microscopy to obtain μm-scale fiber bundle/lamellae orientation from two corneal and six scleral regions. Crimp morphology was quantified through waviness, tortuosity, and amplitude.Whole-globe median waviness, tortuosity, and amplitude were 0.127 radians, 1.002, and 0.273 μm, respectively. These parameters, however, were not uniform over the globe, instead exhibiting distinct, consistent patterns. All crimp parameters decreased significantly with age, with significantly different age-related decreases between regions. The crimp morphology of the limbus changed the most drastically with age, such that it had the largest crimp in neonates, and among the smallest in the elderly.Age-related decreases in crimp parameters are likely one of the mechanisms underlying age-related stiffening of the sclera and cornea, potentially influencing sensitivity to IOP. Further work is needed to determine the biomechanical implications of the crimp patterns observed. The comparatively large changes in the crimp morphology of the limbus, especially in the early years of life, suggest that crimp in this region may play a role in eye development, although the exact nature of this is unclear.

  View details for DOI 10.1167/iovs.17-23474

  View details for PubMedID 30025116

  View details for PubMedCentralID PMC5995484

• Visual Restoration after Cataract Surgery Promotes Functional and Structural Brain Recovery. EBioMedicine Lin, H., Zhang, L., Lin, D., Chen, W., Zhu, Y., Chen, C., Chan, K. C., Liu, Y., Chen, W. 2018; 30: 52-61

  Abstract

  Visual function and brain function decline concurrently with aging. Notably, cataract patients often present with accelerated age-related decreases in brain function, but the underlying mechanisms are still unclear. Optical structures of the anterior segment of the eyes, such as the lens and cornea, can be readily reconstructed to improve refraction and vision quality. However, the effects of visual restoration on human brain function and structure remain largely unexplored.A prospective, controlled clinical trial was conducted. Twenty-six patients with bilateral age-related cataracts (ARCs) who underwent phacoemulsification and intraocular lens implantation and 26 healthy controls without ARC, matched for age, sex, and education, were recruited. Visual functions (including visual acuity, visual evoke potential, and contrast sensitivity), the Mini-Mental State Examination and functional magnetic resonance imaging (including the fractional amplitude of low-frequency fluctuations and grey matter volume variation) were assessed for all the participants and reexamined for ARC patients after cataract surgery. This trial was registered with ClinicalTrials.gov (NCT02644720).Compared with the healthy controls, the ARC patients presented decreased brain functionality as well as structural alterations in visual and cognitive-related brain areas preoperatively. Three months postoperatively, significant functional improvements were observed in the visual and cognitive-related brain areas of the patients. Six months postoperatively, the patients' grey matter volumes in these areas were significantly increased. Notably, both the function and structure in the visual and cognitive-related brain areas of the patients improved significantly and became comparable to those of the healthy controls 6months postoperatively.We demonstrated that ocular reconstruction can functionally and structurally reverse cataract-induced brain changes. The integrity of the eye is essential for maintaining the structure and function of the brain within and beyond the primary visual pathway.

  View details for DOI 10.1016/j.ebiom.2018.03.002

  View details for PubMedID 29548900

  View details for PubMedCentralID PMC5952227

• Macroscale variation in resting-state neuronal activity and connectivity assessed by simultaneous calcium imaging, hemodynamic imaging and electrophysiology. NeuroImage Murphy, M. C., Chan, K. C., Kim, S. G., Vazquez, A. L. 2018; 169: 352-362

  Abstract

  Functional imaging of spontaneous activity continues to play an important role in the field of connectomics. The most common imaging signal used for these experiments is the blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal, but how this signal relates to spontaneous neuronal activity remains incompletely understood. Genetically encoded calcium indicators represent a promising tool to study this problem, as they can provide brain-wide measurements of neuronal activity compared to point measurements afforded by electrophysiological recordings. However, the relationship between the calcium signal and neurophysiological parameters at the mesoscopic scale requires further systematic characterization. Therefore, we collected simultaneous resting-state measurements of electrophysiology, along with calcium and hemodynamic imaging, in lightly anesthetized mice to investigate two aims. First, we examined the relationship between each imaging signal and the simultaneously recorded electrophysiological signal in a single brain region, finding that both signals are better correlated with multi-unit activity compared to local field potentials, with the calcium signal possessing greater signal-to-noise ratio and regional specificity. Second, we used the resting-state imaging data to model the relationship between the calcium and hemodynamic signals across the brain. We found that this relationship varied across brain regions in a way that is consistent across animals, with delays increasing by600 ms towards posterior cortical regions. Furthermore, while overall functional connectivity (FC) measured by the hemodynamic signal is significantly correlated with FC measured by calcium, the two estimates were found to be significantly different. We hypothesize that these differences arise at least in part from the observed regional variation in the hemodynamic response. In total, this work highlights some of the caveats needed in interpreting hemodynamic-based measurements of FC, as well as the need for improved modeling methods to reduce this potential source of bias.

  View details for DOI 10.1016/j.neuroimage.2017.12.070

  View details for PubMedID 29277650

  View details for PubMedCentralID PMC5856618

• Age-related Changes in Eye, Brain and Visuomotor Behavior in the DBA/2J Mouse Model of Chronic Glaucoma. Scientific reports Yang, X. L., van der Merwe, Y., Sims, J., Parra, C., Ho, L. C., Schuman, J. S., Wollstein, G., Lathrop, K. L., Chan, K. C. 2018; 8 (1): 4643

  Abstract

  Although elevated intraocular pressure (IOP) and age are major risk factors for glaucoma, their effects on glaucoma pathogenesis remain unclear. This study examined the onset and progression of glaucomatous changes to ocular anatomy and physiology, structural and physiological brain integrity, and visuomotor behavior in the DBA/2J mice via non-invasive tonometry, multi-parametric magnetic resonance imaging (MRI) and optokinetic assessments from 5 to 12 months of age. Using T2-weighted MRI, diffusion tensor MRI, and manganese-enhanced MRI, increasing IOP elevation at 9 and 12 months old coincided with anterior chamber deepening, altered fractional anisotropy and radial diffusivity of the optic nerve and optic tract, as well as reduced anterograde manganese transport along the visual pathway respectively in the DBA/2J mice. Vitreous body elongation and visuomotor function deterioration were observed until 9 months old, whereas axial diffusivity only decreased at 12 months old in diffusion tensor MRI. Under the same experimental settings, C57BL/6J mice only showed modest age-related changes. Taken together, these results indicate that the anterior and posterior visual pathways of the DBA/2J mice exhibit differential susceptibility to glaucomatous neurodegeneration observable by in vivo multi-modal examinations.

  View details for DOI 10.1038/s41598-018-22850-4

  View details for PubMedID 29545576

  View details for PubMedCentralID PMC5854610

• Longitudinal Assessments of Normal and Perilesional Tissues in Focal Brain Ischemia and Partial Optic Nerve Injury with Manganese-enhanced MRI. Scientific reports Chan, K. C., Zhou, I. Y., Liu, S. S., van der Merwe, Y., Fan, S. J., Hung, V. K., Chung, S. K., Wu, W. T., So, K. F., Wu, E. X. 2017; 7: 43124

  Abstract

  Although manganese (Mn) can enhance brain tissues for improving magnetic resonance imaging (MRI) assessments, the underlying neural mechanisms of Mn detection remain unclear. In this study, we used Mn-enhanced MRI to test the hypothesis that different Mn entry routes and spatiotemporal Mn distributions can reflect different mechanisms of neural circuitry and neurodegeneration in normal and injured brains. Upon systemic administration, exogenous Mn exhibited varying transport rates and continuous redistribution across healthy rodent brain nuclei over a 2-week timeframe, whereas in rodents following photothrombotic cortical injury, transient middle cerebral artery occlusion, or neonatal hypoxic-ischemic brain injury, Mn preferentially accumulated in perilesional tissues expressing gliosis or oxidative stress within days. Intravitreal Mn administration to healthy rodents not only allowed tracing of primary visual pathways, but also enhanced the hippocampus and medial amygdala within a day, whereas partial transection of the optic nerve led to MRI detection of degrading anterograde Mn transport at the primary injury site and the perilesional tissues secondarily over 6 weeks. Taken together, our results indicate the different Mn transport dynamics across widespread projections in normal and diseased brains. Particularly, perilesional brain tissues may attract abnormal Mn accumulation and gradually reduce anterograde Mn transport via specific Mn entry routes.

  View details for DOI 10.1038/srep43124

  View details for PubMedID 28230106

  View details for PubMedCentralID PMC5322351

• Structural and functional correlates of visual field asymmetry in the human brain by diffusion kurtosis MRI and functional MRI. Neuroreport O'Connell, C., Ho, L. C., Murphy, M. C., Conner, I. P., Wollstein, G., Cham, R., Chan, K. C. 2016; 27 (16): 1225-31

  Abstract

  Human visual performance has been observed to show superiority in localized regions of the visual field across many classes of stimuli. However, the underlying neural mechanisms remain unclear. This study aims to determine whether the visual information processing in the human brain is dependent on the location of stimuli in the visual field and the corresponding neuroarchitecture using blood-oxygenation-level-dependent functional MRI (fMRI) and diffusion kurtosis MRI, respectively, in 15 healthy individuals at 3 T. In fMRI, visual stimulation to the lower hemifield showed stronger brain responses and larger brain activation volumes than the upper hemifield, indicative of the differential sensitivity of the human brain across the visual field. In diffusion kurtosis MRI, the brain regions mapping to the lower visual field showed higher mean kurtosis, but not fractional anisotropy or mean diffusivity compared with the upper visual field. These results suggested the different distributions of microstructural organization across visual field brain representations. There was also a strong positive relationship between diffusion kurtosis and fMRI responses in the lower field brain representations. In summary, this study suggested the structural and functional brain involvements in the asymmetry of visual field responses in humans, and is important to the neurophysiological and psychological understanding of human visual information processing.

  View details for DOI 10.1097/WNR.0000000000000682

  View details for PubMedID 27631541

  View details for PubMedCentralID PMC5037044

• In Vivo Evaluation of the Visual Pathway in Streptozotocin-Induced Diabetes by Diffusion Tensor MRI and Contrast Enhanced MRI. PloS one Kancherla, S., Kohler, W. J., van der Merwe, Y., Chan, K. C. 2016; 11 (10): e0165169

  Abstract

  Visual function has been shown to deteriorate prior to the onset of retinopathy in some diabetic patients and experimental animal models. This suggests the involvement of the brain's visual system in the early stages of diabetes. In this study, we tested this hypothesis by examining the integrity of the visual pathway in a diabetic rat model using in vivo multi-modal magnetic resonance imaging (MRI). Ten-week-old Sprague-Dawley rats were divided into an experimental diabetic group by intraperitoneal injection of 65 mg/kg streptozotocin in 0.01 M citric acid, and a sham control group by intraperitoneal injection of citric acid only. One month later, diffusion tensor MRI (DTI) was performed to examine the white matter integrity in the brain, followed by chromium-enhanced MRI of retinal integrity and manganese-enhanced MRI of anterograde manganese transport along the visual pathway. Prior to MRI experiments, the streptozotocin-induced diabetic rats showed significantly smaller weight gain and higher blood glucose level than the control rats. DTI revealed significantly lower fractional anisotropy and higher radial diffusivity in the prechiasmatic optic nerve of the diabetic rats compared to the control rats. No apparent difference was observed in the axial diffusivity of the optic nerve, the chromium enhancement in the retina, or the manganese enhancement in the lateral geniculate nucleus and superior colliculus between groups. Our results suggest that streptozotocin-induced diabetes leads to early injury in the optic nerve when no substantial change in retinal integrity or anterograde transport along the visual pathways was observed in MRI using contrast agent enhancement. DTI may be a useful tool for detecting and monitoring early pathophysiological changes in the visual system of experimental diabetes non-invasively.

  View details for DOI 10.1371/journal.pone.0165169

  View details for PubMedID 27768755

  View details for PubMedCentralID PMC5074510

• Non-invasive MRI Assessments of Tissue Microstructures and Macromolecules in the Eye upon Biomechanical or Biochemical Modulation. Scientific reports Ho, L. C., Sigal, I. A., Jan, N. J., Yang, X., van der Merwe, Y., Yu, Y., Chau, Y., Leung, C. K., Conner, I. P., Jin, T., Wu, E. X., Kim, S. G., Wollstein, G., Schuman, J. S., Chan, K. C. 2016; 6: 32080

  Abstract

  The microstructural organization and composition of the corneoscleral shell (CSS) determine the biomechanical behavior of the eye, and are important in diseases such as glaucoma and myopia. However, limited techniques can assess these properties globally, non-invasively and quantitatively. In this study, we hypothesized that multi-modal magnetic resonance imaging (MRI) can reveal the effects of biomechanical or biochemical modulation on CSS. Upon intraocular pressure (IOP) elevation, CSS appeared hyperintense in both freshly prepared ovine eyes and living rat eyes using T2-weighted MRI. Quantitatively, transverse relaxation time (T2) of CSS increased non-linearly with IOP at 0-40 mmHg and remained longer than unloaded tissues after being unpressurized. IOP loading also increased fractional anisotropy of CSS in diffusion tensor MRI without apparent change in magnetization transfer MRI, suggestive of straightening of microstructural fibers without modification of macromolecular contents. Lastly, treatments with increasing glyceraldehyde (mimicking crosslinking conditions) and chondroitinase-ABC concentrations (mimicking glycosaminoglycan depletion) decreased diffusivities and increased magnetization transfer in cornea, whereas glyceraldehyde also increased magnetization transfer in sclera. In summary, we demonstrated the changing profiles of MRI contrast mechanisms resulting from biomechanical or biochemical modulation of the eye non-invasively. Multi-modal MRI may help evaluate the pathophysiological mechanisms in CSS and the efficacy of corneoscleral treatments.

  View details for DOI 10.1038/srep32080

  View details for PubMedID 27561353

  View details for PubMedCentralID PMC5000015

• Improved spatial accuracy of functional maps in the rat olfactory bulb using supervised machine learning approach. NeuroImage Murphy, M. C., Poplawsky, A. J., Vazquez, A. L., Chan, K. C., Kim, S. G., Fukuda, M. 2016; 137: 1-8

  Abstract

  Functional MRI (fMRI) is a popular and important tool for noninvasive mapping of neural activity. As fMRI measures the hemodynamic response, the resulting activation maps do not perfectly reflect the underlying neural activity. The purpose of this work was to design a data-driven model to improve the spatial accuracy of fMRI maps in the rat olfactory bulb. This system is an ideal choice for this investigation since the bulb circuit is well characterized, allowing for an accurate definition of activity patterns in order to train the model. We generated models for both cerebral blood volume weighted (CBVw) and blood oxygen level dependent (BOLD) fMRI data. The results indicate that the spatial accuracy of the activation maps is either significantly improved or at worst not significantly different when using the learned models compared to a conventional general linear model approach, particularly for BOLD images and activity patterns involving deep layers of the bulb. Furthermore, the activation maps computed by CBVw and BOLD data show increased agreement when using the learned models, lending more confidence to their accuracy. The models presented here could have an immediate impact on studies of the olfactory bulb, but perhaps more importantly, demonstrate the potential for similar flexible, data-driven models to improve the quality of activation maps calculated using fMRI data.

  View details for DOI 10.1016/j.neuroimage.2016.05.055

  View details for PubMedID 27236085

  View details for PubMedCentralID PMC4914461

• Retinal Structures and Visual Cortex Activity are Impaired Prior to Clinical Vision Loss in Glaucoma. Scientific reports Murphy, M. C., Conner, I. P., Teng, C. Y., Lawrence, J. D., Safiullah, Z., Wang, B., Bilonick, R. A., Kim, S. G., Wollstein, G., Schuman, J. S., Chan, K. C. 2016; 6: 31464

  Abstract

  Glaucoma is the second leading cause of blindness worldwide and its pathogenesis remains unclear. In this study, we measured the structure, metabolism and function of the visual system by optical coherence tomography and multi-modal magnetic resonance imaging in healthy subjects and glaucoma patients with different degrees of vision loss. We found that inner retinal layer thinning, optic nerve cupping and reduced visual cortex activity occurred before patients showed visual field impairment. The primary visual cortex also exhibited more severe functional deficits than higher-order visual brain areas in glaucoma. Within the visual cortex, choline metabolism was perturbed along with increasing disease severity in the eye, optic radiation and visual field. In summary, this study showed evidence that glaucoma deterioration is already present in the eye and the brain before substantial vision loss can be detected clinically using current testing methods. In addition, cortical cholinergic abnormalities are involved during trans-neuronal degeneration and can be detected non-invasively in glaucoma. The current results can be of impact for identifying early glaucoma mechanisms, detecting and monitoring pathophysiological events and eye-brain-behavior relationships, and guiding vision preservation strategies in the visual system, which may help reduce the burden of this irreversible but preventable neurodegenerative disease.

  View details for DOI 10.1038/srep31464

  View details for PubMedID 27510406

  View details for PubMedCentralID PMC4980591

• Distribution of Triamcinolone Acetonide after Intravitreal Injection into Silicone Oil-Filled Eye. BioMed research international Da, M., Li, K. K., Chan, K. C., Wu, E. X., Wong, D. S. 2016; 2016: 5485467

  Abstract

  There is increasing use of the vitreous cavity as a reservoir for drug delivery. We study the intraocular migration and distribution of triamcinolone acetonide (TA) after injection into silicone oil tamponade agent during and after vitrectomy surgery ex vivo (pig eye) and in vitro (glass bottle). For ex vivo assessment, intraocular migration of TA was imaged using real-time FLASH MRI scans and high-resolution T2W imaging and the in vitro model was monitored continuously with a video camera. Results of the ex vivo experiment showed that the TA droplet sank to the interface of silicone oil and aqueous almost immediately after injection and remained inside the silicone oil bubble for as long as 16 minutes. The in vitro results showed that, after the shrinkage of the droplet, TA gradually precipitated leaving only a lump of whitish crystalline residue inside the droplet for about 100 minutes. TA then quickly broke the interface and dispersed into the underlying aqueous within 15 seconds, which may result in a momentary increase of local TA concentration in the aqueous portion and potentially toxic to the retina. Our study suggests that silicone oil may not be a good candidate as a drug reservoir for drugs like TA.

  View details for DOI 10.1155/2016/5485467

  View details for PubMedID 27493959

  View details for PubMedCentralID PMC4963566

• MAPS - a Magic Angle Positioning System for Enhanced Imaging in High-Field Small-Bore MRI. Journal of medical robotics research Squires, A., Chan, K. C., Ho, L. C., Sigal, I. A., Jan, N. J., Tse, Z. T. 2016; 1 (1)

  Abstract

  The "magic angle" MRI effect can enhance signal intensity in aligned collagenous structures oriented at approximately 55° with respect to the main magnetic field. The difficulty of positioning tissue inside closed-bore scanners has hampered magic angle use in research and clinics. An MRI-conditional mechatronic system has been developed to control sample orientation inside a 9.4T small bore MRI scanner. The system orients samples to within 0.5° and enables a 600% increase in tendon signal intensity.

  View details for DOI 10.1142/S2424905X16400043

  View details for PubMedID 28713864

  View details for PubMedCentralID PMC5507598

• Top-down influence on the visual cortex of the blind during sensory substitution. NeuroImage Murphy, M. C., Nau, A. C., Fisher, C., Kim, S. G., Schuman, J. S., Chan, K. C. 2016; 125: 932-940

  Abstract

  Visual sensory substitution devices provide a non-surgical and flexible approach to vision rehabilitation in the blind. These devices convert images taken by a camera into cross-modal sensory signals that are presented as a surrogate for direct visual input. While previous work has demonstrated that the visual cortex of blind subjects is recruited during sensory substitution, the cognitive basis of this activation remains incompletely understood. To test the hypothesis that top-down input provides a significant contribution to this activation, we performed functional MRI scanning in 11 blind (7 acquired and 4 congenital) and 11 sighted subjects under two conditions: passive listening of image-encoded soundscapes before sensory substitution training and active interpretation of the same auditory sensory substitution signals after a 10-minute training session. We found that the modulation of visual cortex activity due to active interpretation was significantly stronger in the blind over sighted subjects. In addition, congenitally blind subjects showed stronger task-induced modulation in the visual cortex than acquired blind subjects. In a parallel experiment, we scanned 18 blind (11 acquired and 7 congenital) and 18 sighted subjects at rest to investigate alterations in functional connectivity due to visual deprivation. The results demonstrated that visual cortex connectivity of the blind shifted away from sensory networks and toward known areas of top-down input. Taken together, our data support the model of the brain, including the visual system, as a highly flexible task-based and not sensory-based machine.

  View details for DOI 10.1016/j.neuroimage.2015.11.021

  View details for PubMedID 26584776

  View details for PubMedCentralID PMC5536833

• Structural and Functional Brain Remodeling during Pregnancy with Diffusion Tensor MRI and Resting-State Functional MRI PLOS ONE Chan, R. W., Ho, L. C., Zhou, I. Y., Gao, P. P., Chan, K. C., Wu, E. X. 2015; 10 (12)

  Abstract

  Although pregnancy-induced hormonal changes have been shown to alter the brain at the neuronal level, the exact effects of pregnancy on brain at the tissue level remain unclear. In this study, diffusion tensor imaging (DTI) and resting-state functional MRI (rsfMRI) were employed to investigate and document the effects of pregnancy on the structure and function of the brain tissues. Fifteen Sprague-Dawley female rats were longitudinally studied at three days before mating (baseline) and seventeen days after mating (G17). G17 is equivalent to the early stage of the third trimester in humans. Seven age-matched nulliparous female rats served as non-pregnant controls and were scanned at the same time-points. For DTI, diffusivity was found to generally increase in the whole brain during pregnancy, indicating structural changes at microscopic levels that facilitated water molecular movement. Regionally, mean diffusivity increased more pronouncedly in the dorsal hippocampus while fractional anisotropy in the dorsal dentate gyrus increased significantly during pregnancy. For rsfMRI, bilateral functional connectivity in the hippocampus increased significantly during pregnancy. Moreover, fractional anisotropy increase in the dentate gyrus appeared to correlate with the bilateral functional connectivity increase in the hippocampus. These findings revealed tissue structural modifications in the whole brain during pregnancy, and that the hippocampus was structurally and functionally remodeled in a more marked manner.

  View details for DOI 10.1371/journal.pone.0144328

  View details for Web of Science ID 000366903500020

  View details for PubMedID 26658306

  View details for PubMedCentralID PMC4675543

• Use of sensory substitution devices as a model system for investigating cross-modal neuroplasticity in humans. Neural regeneration research Nau, A. C., Murphy, M. C., Chan, K. C. 2015; 10 (11): 1717-9

  View details for DOI 10.4103/1673-5374.169612

  View details for PubMedID 26807088

  View details for PubMedCentralID PMC4705765

• Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Hung, V. K., Yeung, P. K., Lai, A. K., Ho, M. C., Lo, A. C., Chan, K. C., Wu, E. X., Chung, S. S., Cheung, C. W., Chung, S. K. 2015; 35 (10): 1687-96

  Abstract

  Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

  View details for DOI 10.1038/jcbfm.2015.109

  View details for PubMedID 26104290

  View details for PubMedCentralID PMC4640314

• In Vivo Evaluation of White Matter Integrity and Anterograde Transport in Visual System After Excitotoxic Retinal Injury With Multimodal MRI and OCT. Investigative ophthalmology & visual science Ho, L. C., Wang, B., Conner, I. P., van der Merwe, Y., Bilonick, R. A., Kim, S. G., Wu, E. X., Sigal, I. A., Wollstein, G., Schuman, J. S., Chan, K. C. 2015; 56 (6): 3788-800

  Abstract

  Excitotoxicity has been linked to the pathogenesis of ocular diseases and injuries and may involve early degeneration of both anterior and posterior visual pathways. However, their spatiotemporal relationships remain unclear. We hypothesized that the effects of excitotoxic retinal injury (ERI) on the visual system can be revealed in vivo by diffusion tensor magnetic resonance imagining (DTI), manganese-enhanced magnetic resonance imagining (MRI), and optical coherence tomography (OCT).Diffusion tensor MRI was performed at 9.4 Tesla to monitor white matter integrity changes after unilateral N-methyl-D-aspartate (NMDA)-induced ERI in six Sprague-Dawley rats and six C57BL/6J mice. Additionally, four rats and four mice were intravitreally injected with saline to compare with NMDA-injected animals. Optical coherence tomography of the retina and manganese-enhanced MRI of anterograde transport were evaluated and correlated with DTI parameters.In the rat optic nerve, the largest axial diffusivity decrease and radial diffusivity increase occurred within the first 3 and 7 days post ERI, respectively, suggestive of early axonal degeneration and delayed demyelination. The optic tract showed smaller directional diffusivity changes and weaker DTI correlations with retinal thickness compared with optic nerve, indicative of anterograde degeneration. The splenium of corpus callosum was also reorganized at 4 weeks post ERI. The DTI profiles appeared comparable between rat and mouse models. Furthermore, the NMDA-injured visual pathway showed reduced anterograde manganese transport, which correlated with diffusivity changes along but not perpendicular to optic nerve.Diffusion tensor MRI, manganese-enhanced MRI, and OCT provided an in vivo model system for characterizing the spatiotemporal changes in white matter integrity, the eye-brain relationships and structural-physiological relationships in the visual system after ERI.

  View details for DOI 10.1167/iovs.14-15552

  View details for PubMedID 26066747

  View details for PubMedCentralID PMC4468417

• Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI. Investigative ophthalmology & visual science Chan, K. C., Kancherla, S., Fan, S. J., Wu, E. X. 2014; 56 (1): 1-9

  Abstract

  Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways.Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner.Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres.High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury.

  View details for DOI 10.1167/iovs.14-14287

  View details for PubMedID 25491295

  View details for PubMedCentralID PMC4294285

• Magic angle-enhanced MRI of fibrous microstructures in sclera and cornea with and without intraocular pressure loading. Investigative ophthalmology & visual science Ho, L. C., Sigal, I. A., Jan, N. J., Squires, A., Tse, Z., Wu, E. X., Kim, S. G., Schuman, J. S., Chan, K. C. 2014; 55 (9): 5662-72

  Abstract

  The structure and biomechanics of the sclera and cornea are central to several eye diseases such as glaucoma and myopia. However, their roles remain unclear, partly because of limited noninvasive techniques to assess their fibrous microstructures globally, longitudinally, and quantitatively. We hypothesized that magic angle-enhanced magnetic resonance imaging (MRI) can reveal the structural details of the corneoscleral shell and their changes upon intraocular pressure (IOP) elevation.Seven ovine eyes were extracted and fixed at IOP = 50 mm Hg to mimic ocular hypertension, and another 11 eyes were unpressurized. The sclera and cornea were scanned at different angular orientations relative to the main magnetic field inside a 9.4-Tesla MRI scanner. Relative MRI signal intensities and intrinsic transverse relaxation times (T2 and T2*) were determined to quantify the magic angle effect on the corneoscleral shells. Three loaded and eight unloaded tendon samples were scanned as controls.At magic angle, high-resolution MRI revealed distinct scleral and corneal lamellar fibers, and light/dark bands indicative of collagen fiber crimps in the sclera and tendon. Magic angle enhancement effect was the strongest in tendon and the least strong in cornea. Loaded sclera, cornea, and tendon possessed significantly higher T2 and T2* than unloaded tissues at magic angle.Magic angle-enhanced MRI can detect ocular fibrous microstructures without contrast agents or coatings and can reveal their MR tissue property changes with IOP loading. This technique may open up new avenues for assessment of the biomechanical and biochemical properties of ocular tissues in aging and in diseases involving the corneoscleral shell.

  View details for DOI 10.1167/iovs.14-14561

  View details for PubMedID 25103267

  View details for PubMedCentralID PMC4160095

• Successful tactile based visual sensory substitution use functions independently of visual pathway integrity. Frontiers in human neuroscience Lee, V. K., Nau, A. C., Laymon, C., Chan, K. C., Rosario, B. L., Fisher, C. 2014; 8: 291

  Abstract

  Neuronal reorganization after blindness is of critical interest because it has implications for the rational prescription of artificial vision devices. The purpose of this study was to distinguish the microstructural differences between perinatally blind (PB), acquired blind (AB), and normally sighted controls (SCs) and relate these differences to performance on functional tasks using a sensory substitution device (BrainPort).We enrolled 52 subjects (PB n = 11; AB n = 35; SC n = 6). All subjects spent 15 h undergoing BrainPort device training. Outcomes of light perception, motion, direction, temporal resolution, grating, and acuity were tested at baseline and after training. Twenty-six of the subjects were scanned with a three Tesla MRI scanner for diffusion tensor imaging (DTI), and with a positron emission tomography (PET) scanner for mapping regional brain glucose consumption during sensory substitution function. Non-parametric models were used to analyze fractional anisotropy (FA; a DTI measure of microstructural integrity) of the brain via region-of-interest (ROI) analysis and tract-based spatial statistics (TBSS).At baseline, all subjects performed all tasks at chance level. After training, light perception, time resolution, location and grating acuity tasks improved significantly for all subject groups. ROI and TBSS analyses of FA maps show areas of statistically significant differences (p ≤ 0.025) in the bilateral optic radiations and some visual association connections between all three groups. No relationship was found between FA and functional performance with the BrainPort.All subjects showed performance improvements using the BrainPort irrespective of nature and duration of blindness. Definite brain areas with significant microstructural integrity changes exist among PB, AB, and NC, and these variations are most pronounced in the visual pathways. However, the use of sensory substitution devices is feasible irrespective of microstructural integrity of the primary visual pathways between the eye and the brain. Therefore, tongue based devices devices may be usable for a broad array of non-sighted patients.

  View details for DOI 10.3389/fnhum.2014.00291

  View details for PubMedID 24860473

  View details for PubMedCentralID PMC4026734

• In vivo assessment of aqueous humor dynamics upon chronic ocular hypertension and hypotensive drug treatment using gadolinium-enhanced MRI. Investigative ophthalmology & visual science Ho, L. C., Conner, I. P., Do, C. W., Kim, S. G., Wu, E. X., Wollstein, G., Schuman, J. S., Chan, K. C. 2014; 55 (6): 3747-57

  Abstract

  Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions.Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood-aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes.Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous-vitreous or blood-ocular barrier integrity.Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments.

  View details for DOI 10.1167/iovs.14-14263

  View details for PubMedID 24764067

  View details for PubMedCentralID PMC4062398

• In vivo visuotopic brain mapping with manganese-enhanced MRI and resting-state functional connectivity MRI NEUROIMAGE Chan, K. C., Fan, S., Chan, R. W., Cheng, J. S., Zhou, I. Y., Wu, E. X. 2014; 90: 235-245

  Abstract

  The rodents are an increasingly important model for understanding the mechanisms of development, plasticity, functional specialization and disease in the visual system. However, limited tools have been available for assessing the structural and functional connectivity of the visual brain network globally, in vivo and longitudinally. There are also ongoing debates on whether functional brain connectivity directly reflects structural brain connectivity. In this study, we explored the feasibility of manganese-enhanced MRI (MEMRI) via 3 different routes of Mn(2+) administration for visuotopic brain mapping and understanding of physiological transport in normal and visually deprived adult rats. In addition, resting-state functional connectivity MRI (RSfcMRI) was performed to evaluate the intrinsic functional network and structural-functional relationships in the corresponding anatomical visual brain connections traced by MEMRI. Upon intravitreal, subcortical, and intracortical Mn(2+) injection, different topographic and layer-specific Mn enhancement patterns could be revealed in the visual cortex and subcortical visual nuclei along retinal, callosal, cortico-subcortical, transsynaptic and intracortical horizontal connections. Loss of visual input upon monocular enucleation to adult rats appeared to reduce interhemispheric polysynaptic Mn(2+) transfer but not intra- or inter-hemispheric monosynaptic Mn(2+) transport after Mn(2+) injection into visual cortex. In normal adults, both structural and functional connectivity by MEMRI and RSfcMRI was stronger interhemispherically between bilateral primary/secondary visual cortex (V1/V2) transition zones (TZ) than between V1/V2 TZ and other cortical nuclei. Intrahemispherically, structural and functional connectivity was stronger between visual cortex and subcortical visual nuclei than between visual cortex and other subcortical nuclei. The current results demonstrated the sensitivity of MEMRI and RSfcMRI for assessing the neuroarchitecture, neurophysiology and structural-functional relationships of the visual brains in vivo. These may possess great potentials for effective monitoring and understanding of the basic anatomical and functional connections in the visual system during development, plasticity, disease, pharmacological interventions and genetic modifications in future studies.

  View details for DOI 10.1016/j.neuroimage.2013.12.056

  View details for Web of Science ID 000338909500024

  View details for PubMedID 24394694

  View details for PubMedCentralID PMC3951771

• In vivo chromium-enhanced MRI of the retina. Magnetic resonance in medicine Chan, K. C., Fan, S. J., Zhou, I. Y., Wu, E. X. 2012; 68 (4): 1202-10

  Abstract

  Chromium (Cr) has been used histologically to stabilize lipid fractions in the retina and is suggested to enhance oxidizable lipids in brain MRI. This study explored the feasibility, sensitivity, and specificity of in vivo chromium-enhanced MRI of retinal lipids by determining its spatiotemporal profiles and toxic effect after intravitreal Cr(VI) injection to normal adult rats. One day after 3 μL Cr(VI) administration at 1-100 mM, the retina exhibited a dose-dependent increase in T1-weighted hyperintensity until 50 mM. Time-dependently, significant T1-weighted hyperintensity persisted up to 2 weeks after 10 mM Cr(VI) administration. Three-dimensional chromium-enhanced MRI of ex vivo normal eyes at isotropic 50-μm resolution showed at least five alternating bands across retinal layers, with the outermost layer being the brightest. This agreed with histology indicating alternating lipid contents with the highest level in the photoreceptor layer of the outer retina. Although Cr(VI) reduction may induce oxidative stress and depolymerize microtubules, manganese-enhanced MRI after chromium-enhanced MRI showed a dose-dependent effect of Cr toxicity on manganese uptake and axonal transport along the visual pathway. These results potentiated future longitudinal chromium-enhanced MRI studies on retinal lipid metabolism upon further optimization of Cr doses with visual cell viability.

  View details for DOI 10.1002/mrm.24123

  View details for PubMedID 22213133

• Effect of cerebrovascular changes on brain DTI quantitation: a hypercapnia study. Magnetic resonance imaging Ding, A. Y., Chan, K. C., Wu, E. X. 2012; 30 (7): 993-1001

  Abstract

  Quantitative diffusion tensor imaging (DTI) offers a valuable tool to probe the microstructural changes in neural tissues in vivo, where absolute quantitation accuracy and reproducibility are essential. It has been long recognized that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced by the presence of water molecules in cerebrovasculature. However, little is known about to what extent such blood signal affects DTI quantitation. In this study, we quantitatively examined the effect of cerebral hemodynamic change on DTI indices by using a standard multislice echo planar imaging (EPI) spin echo (SE) DTI acquisition protocol and a rat model of hypercapnia. In response to 5% CO(2) challenge, mean, radial and axial diffusivities measured with diffusion factor (b-value) of b=1.0 ms/μm(2) were found to increase in whole brain (1.52%±0.22%, 1.66%±0.16% and 1.35%±0.37%, respectively), gray matter (1.56%±0.23%, 1.63%±0.14% and 1.47%±0.45%, respectively) and white matter regions (1.45%±0.28%, 1.88%±0.33% and 1.10%±0.26%, respectively). Fractional anisotropy (FA) was found to decrease by 1.67%±0.38%, 1.91%±0.59% and 1.46%±0.30% in whole brain, gray matter and white matter regions, respectively. In addition, these diffusivity increases and FA decreases became more pronounced at a lower b-value (b=0.3 ms/μm(2)). The results indicated that in vivo DTI quantitation in brain can be contaminated by vascular factors on the order of few percentages. Consequently, alterations in cerebrovasculature and hemodynamics can affect the DTI quantitation and its efficacy in characterizing the neural tissue microstructures in normal and diseased states. Caution should be taken in designing and interpreting quantitative DTI studies as all DTI indices can be potentially confounded by physiologic conditions and by cerebrovascular and hemodynamic characteristics.

  View details for DOI 10.1016/j.mri.2012.02.012

  View details for PubMedID 22495243

• High fidelity tonotopic mapping using swept source functional magnetic resonance imaging. NeuroImage Cheung, M. M., Lau, C., Zhou, I. Y., Chan, K. C., Zhang, J. W., Fan, S. J., Wu, E. X. 2012; 61 (4): 978-86

  Abstract

  Tonotopy, the topographic encoding of sound frequency, is the fundamental property of the auditory system. Invasive techniques lack the spatial coverage or frequency resolution to rigorously investigate tonotopy. Conventional auditory fMRI is corrupted by significant image distortion, sporadic acoustic noise and inadequate frequency resolution. We developed an efficient and high fidelity auditory fMRI method that integrates continuous frequency sweeping stimulus, distortion free MRI sequence with stable scanner noise and Fourier analysis. We demonstrated this swept source imaging (SSI) in the rat inferior colliculus and obtained tonotopic maps with ~2 kHz resolution and 40 kHz bandwidth. The results were vastly superior to those obtained by conventional fMRI mapping approach and in excellent agreement with invasive findings. We applied SSI to examine tonotopic injury following developmental noise exposure and observed that the tonotopic organization was significantly disrupted. With SSI, we also observed the subtle effects of sound pressure level on tonotopic maps, reflecting the complex neuronal responses associated with asymmetric tuning curves. This in vivo and noninvasive technique will greatly facilitate future investigation of tonotopic plasticity and disorders and auditory information processing. SSI can also be adapted to study topographic organization in other sensory systems such as retinotopy and somatotopy.

  View details for DOI 10.1016/j.neuroimage.2012.03.031

  View details for PubMedID 22445952

• Balanced steady-state free precession fMRI with intravascular susceptibility contrast agent. Magnetic resonance in medicine Zhou, I. Y., Cheung, M. M., Lau, C., Chan, K. C., Wu, E. X. 2012; 68 (1): 65-73

  Abstract

  One major challenge in echo planar imaging-based functional MRI (fMRI) is the susceptibility-induced image distortion. In this study, a new cerebral blood volume-weighted fMRI technique using distortion-free balanced steady-state free precession (bSSFP) sequence was proposed and its feasibility was investigated in rat brain at 7 Tesla. After administration of intravascular susceptibility contrast agent (monocrystalline iron oxide nanoparticle [MION] at 15 mg/kg), unilateral visual stimulation was presented using a block-design paradigm. With repetition time/echo time = 3.8/1.9 ms and α = 18°, bSSFP fMRI was performed and compared with the conventional cerebral blood volume-weighted fMRI using post-MION gradient echo and spin echo echo planar imaging. The results showed that post-MION bSSFP fMRI provides comparable sensitivity but with no severe image distortion and signal dropout. Robust negative responses were observed during stimulation and activation patterns were in excellent agreement with known neuroanatomy. Furthermore, the post-MION bSSFP signal was observed to decrease significantly during hypercapnia challenge, indicating its sensitivity to cerebral blood volume changes. These findings demonstrated that post-MION bSSFP fMRI is a promising alternative to conventional cerebral blood volume-weighted fMRI. This technique is particularly suited for fMRI investigation of animal models at high field.

  View details for DOI 10.1002/mrm.23202

  View details for PubMedID 22127794

• BOLD fMRI investigation of the rat auditory pathway and tonotopic organization. NeuroImage Cheung, M. M., Lau, C., Zhou, I. Y., Chan, K. C., Cheng, J. S., Zhang, J. W., Ho, L. C., Wu, E. X. 2012; 60 (2): 1205-11

  Abstract

  Rodents share general anatomical, physiological and behavioral features in the central auditory system with humans. In this study, monaural broadband noise and pure tone sounds are presented to normal rats and the resulting hemodynamic responses are measured with blood oxygenation level-dependent (BOLD) fMRI using a standard spin-echo echo planar imaging sequence (without sparse temporal sampling). The cochlear nucleus (CN), superior olivary complex, lateral lemniscus, inferior colliculus (IC), medial geniculate body and primary auditory cortex, all major auditory structures, are activated by broadband stimulation. The CN and IC BOLD signal changes increase monotonically with sound pressure level. Pure tone stimulation with three distinct frequencies (7, 20 and 40 kHz) reveals the tonotopic organization of the IC. The activated regions shift from dorsolateral to ventromedial IC with increasing frequency. These results agree with electrophysiology and immunohistochemistry findings, indicating the feasibility of auditory fMRI in rats. This is the first fMRI study of the rodent ascending auditory pathway.

  View details for DOI 10.1016/j.neuroimage.2012.01.087

  View details for PubMedID 22297205

• In vivo evaluation of retinal and callosal projections in early postnatal development and plasticity using manganese-enhanced MRI and diffusion tensor imaging. NeuroImage Chan, K. C., Cheng, J. S., Fan, S., Zhou, I. Y., Yang, J., Wu, E. X. 2012; 59 (3): 2274-83

  Abstract

  The rodents are an excellent model for understanding the development and plasticity of the visual system. In this study, we explored the feasibility of Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) at 7 T for in vivo and longitudinal assessments of the retinal and callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Along the retinal pathways, unilateral intravitreal Mn2+ injection resulted in Mn2+ uptake and transport in normal neonatal visual brains at postnatal days (P) 1, 5 and 10 with faster Mn2+ clearance than the adult brains at P60. The reorganization of retinocollicular projections was also detected by significant Mn2+ enhancement by 2%-10% in the ipsilateral superior colliculus (SC) of normal neonatal rats, normal adult mice and adult rats after neonatal monocular enucleation (ME) but not in normal adult rats or adult rats after monocular deprivation (MD). DTI showed a significantly higher fractional anisotropy (FA) by 21% in the optic nerve projected from the remaining eye of ME rats compared to normal rats at 6 weeks old, likely as a result of the retention of axons from the ipsilaterally uncrossed retinal ganglion cells, whereas the anterior and posterior retinal pathways projected from the enucleated or deprived eyes possessed lower FA after neonatal binocular enucleation (BE), ME and MD by 22%-56%, 18%-46% and 11%-15% respectively compared to normal rats, indicative of neurodegeneration or immaturity of white matter tracts. Along the visual callosal pathways, intracortical Mn2+ injection to the visual cortex of BE rats enhanced a larger projection volume by about 74% in the V1/V2 transition zone of the contralateral hemisphere compared to normal rats, without apparent DTI parametric changes in the splenium of corpus callosum. This suggested an adaptive change in interhemispheric connections and spatial specificity in the visual cortex upon early blindness. The results of this study may help determine the mechanisms of axonal uptake and transport, microstructural reorganization and functional activities in the living visual brains during development, diseases, plasticity and early interventions in a global and longitudinal setting.

  View details for DOI 10.1016/j.neuroimage.2011.09.055

  View details for PubMedID 21985904

• BOLD responses in the superior colliculus and lateral geniculate nucleus of the rat viewing an apparent motion stimulus. NeuroImage Lau, C., Zhang, J. W., Xing, K. K., Zhou, I. Y., Cheung, M. M., Chan, K. C., Wu, E. X. 2011; 58 (3): 878-84

  Abstract

  In rats, the superior colliculus (SC) is a main destination for retinal ganglion cells and is an important subcortical structure for vision. Electrophysiology studies have observed that many SC neurons are highly sensitive to moving objects, but complementary non-invasive functional imaging studies with larger fields of view have been rarely conducted. In this study, BOLD fMRI is used to measure the SC and nearby lateral geniculate nucleus' (LGN) hemodynamic responses, in normal adult Sprague Dawley (SD) rats, during a dynamic visual stimulus similar to those used in long-range apparent motion studies. The stimulation paradigm consists of four light spots arranged in a linear array and turned on and off sequentially at different rates to create five effective speeds of motion (7, 14, 41, 82, and 164°/s across the visual field). Stationary periods (same light spot always on) are interleaved between the moving periods. The speed response function (SRF), the hemodynamic response amplitude at each speed tested, is measured. Significant responses are observed in the SC and LGN at all speeds. In the SC, the SRF increases monotonically from 7 to 82°/s. The minimum response amplitude occurs at 164°/s. The results suggest that the SC is sensitive to slow moving visual stimuli but the hemodynamic response is reduced at higher speeds. In the LGN, the SRF exhibits a similar trend to that of the SC, but response amplitude during 7°/s stimulation is comparable to that during 164°/s stimulation. These findings are in good agreement with previous electrophysiology studies conducted on albino rats like the SD strain. This work represents the first fMRI study of stimulus speed dependence in the SC and is also the first fMRI study of motion responsiveness in the rat.

  View details for DOI 10.1016/j.neuroimage.2011.06.055

  View details for PubMedID 21741483

• CNS regeneration after chronic injury using a self-assembled nanomaterial and MEMRI for real-time in vivo monitoring. Nanomedicine : nanotechnology, biology, and medicine Liang, Y. X., Cheung, S. W., Chan, K. C., Wu, E. X., Tay, D. K., Ellis-Behnke, R. G. 2011; 7 (3): 351-9

  Abstract

  To speed up the process of central nervous system (CNS) recovery after injury, the need for real-time measurement of axon regeneration in vivo is essential to assess the extent of injury, as well as the optimal timing and delivery of therapeutics and rehabilitation. It was necessary to develop a chronic animal model with an in vivo measurement technique to provide a real-time monitoring and feedback system. Using the framework of the 4 P's of CNS regeneration (Preserve, Permit, Promote and Plasticity) as a guide, combined with noninvasive manganese-enhanced magnetic resonance imaging (MEMRI), we show a successful chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. We also show that a chronic optic tract (OT) lesion is able to heal, and axons are able to regenerate, when treated with a self-assembling nanofiber peptide scaffold (SAPNS).The authors of this study demonstrate the development of a chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. In addition, they determined that chronic optic tract lesions are able to heal with axonal regeneration when treated with a self-assembling nanofiber peptide scaffold (SAPNS).

  View details for DOI 10.1016/j.nano.2010.12.001

  View details for PubMedID 21185404

• BOLD temporal dynamics of rat superior colliculus and lateral geniculate nucleus following short duration visual stimulation. PloS one Lau, C., Zhou, I. Y., Cheung, M. M., Chan, K. C., Wu, E. X. 2011; 6 (4): e18914

  Abstract

  The superior colliculus (SC) and lateral geniculate nucleus (LGN) are important subcortical structures for vision. Much of our understanding of vision was obtained using invasive and small field of view (FOV) techniques. In this study, we use non-invasive, large FOV blood oxygenation level-dependent (BOLD) fMRI to measure the SC and LGN's response temporal dynamics following short duration (1 s) visual stimulation.Experiments are performed at 7 tesla on Sprague Dawley rats stimulated in one eye with flashing light. Gradient-echo and spin-echo sequences are used to provide complementary information. An anatomical image is acquired from one rat after injection of monocrystalline iron oxide nanoparticles (MION), a blood vessel contrast agent. BOLD responses are concentrated in the contralateral SC and LGN. The SC BOLD signal measured with gradient-echo rises to 50% of maximum amplitude (PEAK) 0.2±0.2 s before the LGN signal (p<0.05). The LGN signal returns to 50% of PEAK 1.4±1.2 s before the SC signal (p<0.05). These results indicate the SC signal rises faster than the LGN signal but settles slower. Spin-echo results support these findings. The post-MION image shows the SC and LGN lie beneath large blood vessels. This subcortical vasculature is similar to that in the cortex, which also lies beneath large vessels. The LGN lies closer to the large vessels than much of the SC.The differences in response timing between SC and LGN are very similar to those between deep and shallow cortical layers following electrical stimulation, which are related to depth-dependent blood vessel dilation rates. This combined with the similarities in vasculature between subcortex and cortex suggest the SC and LGN timing differences are also related to depth-dependent dilation rates. This study shows for the first time that BOLD responses in the rat SC and LGN following short duration visual stimulation are temporally different.

  View details for DOI 10.1371/journal.pone.0018914

  View details for PubMedID 21559482

  View details for PubMedCentralID PMC3084720

• Metabolic changes in visual cortex of neonatal monocular enucleated rat: a proton magnetic resonance spectroscopy study. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience Chow, A. M., Zhou, I. Y., Fan, S. J., Chan, K. W., Chan, K. C., Wu, E. X. 2011; 29 (1): 25-30

  Abstract

  Neonatal monocular enucleation (ME) is often employed to study the developmental mechanisms underlying visual perception and the cross-modal changes in the central nervous system caused by early loss of the visual input. However, underlying biochemical or metabolic mechanisms that accompany the morphological, physiological and behavioral changes after ME are not fully understood. Male Sprague-Dawley rats (N=14) were prepared and divided into 2 groups. The enucleated group (N=8) underwent right ME (right eye removal) at postnatal day 10, while the normal group (N=6) was intact and served as a control. Three weeks after ME, single voxel proton magnetic resonance spectroscopy ((1)H MRS) was performed over the visual cortex of each hemisphere in all animals with a point-resolved spectroscopy (PRESS) sequence at 7 T. The taurine (Tau) and N-acetylaspartate (NAA) levels were found to be significantly lower in the left visual cortex (contralateral to enucleated eye) for enucleated animals. Such metabolic changes measured in vivo likely reflected the cortical degeneration associated with the reduction of neurons, axon terminals and overall neuronal activity. This study also demonstrated that (1)H MRS approach has the potential to characterize neonatal ME and other developmental neuroplasticity models noninvasively for the biochemical and metabolic processes involved.

  View details for DOI 10.1016/j.ijdevneu.2010.10.002

  View details for PubMedID 20950681

• In vivo retinotopic mapping of superior colliculus using manganese-enhanced magnetic resonance imaging. NeuroImage Chan, K. C., Li, J., Kau, P., Zhou, I. Y., Cheung, M. M., Lau, C., Yang, J., So, K. F., Wu, E. X. 2011; 54 (1): 389-95

  Abstract

  The superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, whose superficial layers receive visual information from the retina in a topological order. Despite the increasing number of studies investigating retinotopic projection in visual brain development and disorders, in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei has not yet been available. This study explores the capability of 3D manganese-enhanced MRI (MEMRI) at 200 μm isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn(2+) injection into both eyes, animals with partial transection at the right superior intraorbital optic nerve in Group 1 (n=8) exhibited a significantly lower T1-weighted signal intensity in the lateral region of the left SC compared to the left medial SC and right control SC. Partial transection toward the temporal or nasal region of the right intraorbital optic nerve in Group 2 (n=7) led to T1-weighted hypointensity in the rostral or caudal region of the left SC, whereas a clear border was observed separating 2 halves of the left SC in all groups. Previous histological and electrophysiological studies showed that the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected respectively to the contralateral lateral, medial, caudal and rostral SC in rodents. While this topological pattern is preserved in the intraorbital optic nerve, it was shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly in the superior but not inferior retina and optic nerve. The results of this study demonstrated the sensitivity of submillimeter-resolution MEMRI for in vivo, 3D mapping of the precise retinotopic projections in SC upon reduced anterograde axonal transport of Mn(2+) ions from localized regions of the anterior visual pathways to the subcortical midbrain nuclei. Future MEMRI studies are envisioned that measure the topographic changes in brain development, diseases, plasticity and regeneration therapies in a global and longitudinal setting.

  View details for DOI 10.1016/j.neuroimage.2010.07.015

  View details for PubMedID 20633657

• Magnetic resonance spectroscopy of the brain under mild hypothermia indicates changes in neuroprotection-related metabolites. Neuroscience letters Chan, K. W., Chow, A. M., Chan, K. C., Yang, J., Wu, E. X. 2010; 475 (3): 150-5

  Abstract

  Brain hypothermia has demonstrated pronounced neuroprotective effect in patients with cardiac arrest, ischemia and acute liver failure. However, its underlying neuroprotective mechanisms remain to be elucidated in order to improve therapeutic outcomes. Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) was performed using a 7 Tesla MRI scanner on normal Sprague-Dawley rats (N=8) in the same voxel under normothermia (36.5 degrees C) and 30min mild hypothermia (33.5 degrees C). Levels of various brain proton metabolites were compared. The level of lactate (Lac) and myo-inositol (mI) increased in the cortex during hypothermia. In the thalamus, taurine (Tau), a cryogen in brain, increased and choline (Cho) decreased. These metabolic alterations indicated the onset of a number of neuroprotective processes that include attenuation of energy metabolism, excitotoxic pathways, brain osmolytes and thermoregulation, thus protecting neuronal cells from damage. These experimental findings demonstrated that (1)H-MRS can be applied to investigate the changes of specific metabolites and corresponding neuroprotection mechanisms in vivo noninvasively, and ultimately improve our basic understanding of hypothermia and ability to optimize its therapeutic efficacy.

  View details for DOI 10.1016/j.neulet.2010.03.066

  View details for PubMedID 20362032

• Functional MRI of postnatal visual development in normal and hypoxic-ischemic-injured superior colliculi. NeuroImage Chan, K. C., Xing, K. K., Cheung, M. M., Zhou, I. Y., Wu, E. X. 2010; 49 (3): 2013-20

  Abstract

  The superior colliculus (SC) is a laminated subcortical structure in the mammalian midbrain, whose superficial layers receive visual information from the retina and the visual cortex. To date, its functional organization and development in the visual system remain largely unknown. This study employed blood oxygenation level-dependent (BOLD) functional MRI to evaluate the visual responses of the SC in normally developing and severe neonatal hypoxic-ischemic (HI)-injured rat brains from the time of eyelid opening to adulthood. MRI was performed to the normal animals (n=7) at postnatal days (P) 14, 21, 28 and 60. In the HI-injured group (n=7), the ipsilesional primary and secondary visual cortices were completely damaged after unilateral ligation of the left common carotid artery at P7 followed by hypoxia for 2 h, and MRI was performed at P60. Upon unilateral flash illumination, the normal contralateral SC underwent a systematic increase in BOLD signal amplitude with age especially after the third postnatal week. However, no significant difference in BOLD signal increase was found between P14 and P21. These findings implied the presence of neurovascular coupling at the time of eyelid opening, and the progressive development of hemodynamic regulation in the subcortical visual system. In the HI-injured group at P60, the BOLD signal increases in both SC remained at the same level as the normal group at P28 though they were significantly lower than the normal group at P60. These observations suggested the residual visual functions on both sides of the subcortical brain, despite the damages to the entire ipsilesional visual cortex. The results of this study constitute important evidence on the progressive maturation of visual functions and hemodynamic responses in the normal subcortical brain, and its functional plasticity upon neonatal HI injury.

  View details for DOI 10.1016/j.neuroimage.2009.10.069

  View details for PubMedID 19879366

• B-value dependence of DTI quantitation and sensitivity in detecting neural tissue changes. NeuroImage Hui, E. S., Cheung, M. M., Chan, K. C., Wu, E. X. 2010; 49 (3): 2366-74

  Abstract

  Recently, remarkable success has been demonstrated in using MR diffusion tensor imaging (DTI) to characterize white matter. Water diffusion in complex biological tissue microstructure is not a free or Gaussian process but is hindered and restricted, thus contradicting the basic assumption in conventional DTI that diffusion weighted signal decays with b-value in a monoexponential manner. Nevertheless, DTI by far is still the fastest and most robust protocol in routine research and clinical settings. To assess the b-value dependence of DTI indices and evaluate their sensitivities in detecting neural tissues changes, in vivo DTI data acquired from rat brains at postnatal day 13, 21 and 120 with different b-values (0.5-2.5 ms/microm(2)) and 30 gradient directions were analyzed. Results showed that the mean and directional diffusivities consistently decreased with b-value in both white and gray matters. The sensitivity of axial diffusivity (lambda(//)) in monitoring brain maturation generally decreased with b-value whereas that of radial diffusivity (lambda( perpendicular)) increased. FA generally varied less with b-value but in a manner dependent of the age and tissue type. Analysis also revealed that the FA sensitivity in detecting specific tissue changes was affected by b-value. These experimental findings confirmed the crucial effect of b-value on quantitative DTI in monitoring neural tissue alterations. They suggested that the choice of b-value in conventional DTI acquisition can be optimized for detecting neural tissue changes but shall depend on the specific tissue type and its changes or pathologies targeted, and caution must be taken in interpreting DTI indices.

  View details for DOI 10.1016/j.neuroimage.2009.10.022

  View details for PubMedID 19837181

• Late measures of microstructural alterations in severe neonatal hypoxic-ischemic encephalopathy by MR diffusion tensor imaging INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE Chan, K. C., Khong, P., Lau, H., Cheung, P., Wu, E. X. 2009; 27 (6): 607-615

  Abstract

  Neonatal hypoxic-ischemic encephalopathy is a major cause of brain damage in infants, and is associated with periventricular white matter injury and chronic neurological dysfunctions. However, the mechanisms of the chronic white matter injury and reorganization are still unclear. In this study, in vivo diffusion tensor imaging (DTI) was employed to evaluate the late changes of white matter microstructural integrity in the rat brains at 10 weeks after severe neonatal hypoxic-ischemic insults at postnatal day 7. In the fractional anisotropy directionality map, qualitative evaluation showed that a dorsoventrally oriented fiber bundle extended from the corpus callosum into the cyst in the anterior brain, whilst the posterior peri-infarct areas had similar fiber orientations as the contralateral internal capsule, optic tract and fimbria of hippocampus. Compared to the contralateral hemisphere, significantly higher fractional anisotropy, axial diffusivity and diffusion trace value were observed quantitatively in the distal end of the extended fiber bundle connecting the anterior and posterior white matters rostrocaudally. A significantly lower fractional anisotropy but higher axial and radial diffusivities and trace were also found in the ipsilateral corpus callosum, proximal external capsule and anterior commissure, while slightly lower fractional anisotropy and axial diffusivity were noticed in the ipsilateral internal capsule and optic nerve. It was suggested that increased fractional anisotropy, axial diffusivity and trace characterize white matter reorganization in chronic neonatal hypoxic-ischemic insults, whereas reduction in fractional anisotropy appears to characterize two types of white matter lesions, with significantly higher axial and radial diffusivities and trace being primary and slightly lower axial diffusivity being secondary. Combined with fractional anisotropy directionality map, in vivo DTI provides important indices to differentiate the chronic effects of severe neonatal hypoxic-ischemic injury and recovery globally, quantitatively and non-invasively.

  View details for DOI 10.1016/j.ijdevneu.2009.05.012

  View details for Web of Science ID 000269816300013

  View details for PubMedID 19505567

• Myocardial T2 quantitation in patients with iron overload at 3 Tesla. Journal of magnetic resonance imaging : JMRI Guo, H., Au, W. Y., Cheung, J. S., Kim, D., Jensen, J. H., Khong, P. L., Chan, Q., Chan, K. C., Tosti, C., Tang, H., Brown, T. R., Lam, W. W., Ha, S. Y., Brittenham, G. M., Wu, E. X. 2009; 30 (2): 394-400

  Abstract

  To investigate the feasibility of measuring myocardial T2 at 3 Tesla for assessment of tissue iron in thalassemia major and other iron overloaded patients.A single-breathhold electrocardiogram-triggered black-blood multi-echo spin-echo (MESE) sequence with a turbo factor of 2 was implemented at 3 Tesla (T). Myocardial and liver T2 values were measured with three repeated breathholds in 8 normal subjects and 24 patients. Their values, together with the T2 values measured using a breathhold multi-echo gradient-echo sequence, were compared with those at 1.5T in the same patients.At 3T, myocardial T2 was found to be 39.6 +/- 7.4 ms in normal subjects. In patients, it ranged from 12.9 to 50.1 ms. "T2 and T2(*) [corrected] were observed to correlate in heart (rho = 0.93, P [corrected] < 0.0001) and liver (rho = 0.95, P < 0.0001). Myocardial T2 and T2 at 3T were also highly correlated with the 1.5T measurements. Preliminary results indicated that myocardial T2 quantitation was relatively insensitive to B1 variation, and reproducible with 3.2% intra-exam and 3.8% inter-exam variations.Myocardial T2 quantitation is feasible at 3T. Given the substantially decreased T2 and increased B0 inhomogeneity, the rapid myocardial T2 measurement protocol demonstrated here may present a robust alternative to study cardiac iron overload at 3T.

  View details for DOI 10.1002/jmri.21851

  View details for PubMedID 19629983

  View details for PubMedCentralID PMC2946793

• MRI of late microstructural and metabolic alterations in radiation-induced brain injuries. Journal of magnetic resonance imaging : JMRI Chan, K. C., Khong, P. L., Cheung, M. M., Wang, S., Cai, K. X., Wu, E. X. 2009; 29 (5): 1013-20

  Abstract

  To evaluate the late effects of radiation-induced damages in the rat brain by means of in vivo multiparametric MRI.The right hemibrains of seven Sprague-Dawley rats were irradiated with a highly collimated 6 MV photon beam at a single dose of approximately 28 Gy. Diffusion tensor imaging (DTI), proton MR spectroscopy ((1)H-MRS), T2-weighted imaging, and T1-weighted imaging were performed to the same animals 12 months after radiation treatment.Compared with the contralateral side, a significantly higher percentage decrease in fractional anisotropy was observed in the ipsilateral fimbria of hippocampus (29%) than the external capsule (8%) in DTI, indicating the selective vulnerability of fimbria to radiation treatment. Furthermore, in (1)H-MRS, significantly higher choline, glutamate, lactate, and taurine peaks by 24%, 25%, 87%, and 58%, respectively, were observed relative to creatine in the ipsilateral brain. Postmortem histology confirmed these white matter degradations as well as glial fibrillary acidic protein and glutamine synthetase immunoreactivity increase in the ipsilateral brain.The microstructural and metabolic changes in late radiation-induced brain injuries were documented in vivo. These multiparametric MRI measurements may help understand the white matter changes and neurotoxicity upon radiation treatment in a single setting.

  View details for DOI 10.1002/jmri.21736

  View details for PubMedID 19388094

• Does diffusion kurtosis imaging lead to better neural tissue characterization? A rodent brain maturation study. NeuroImage Cheung, M. M., Hui, E. S., Chan, K. C., Helpern, J. A., Qi, L., Wu, E. X. 2009; 45 (2): 386-92

  Abstract

  Diffusion kurtosis imaging (DKI) can be used to estimate excess kurtosis, which is a dimensionless measure for the deviation of water diffusion profile from Gaussian distribution. Several recent studies have applied DKI to probe the restricted water diffusion in biological tissues. The directional analysis has also been developed to obtain the directionally specific kurtosis. However, these studies could not directly evaluate the sensitivity of DKI in detecting subtle neural tissue alterations. Brain maturation is known to involve various biological events that can affect water diffusion properties, thus providing a sensitive platform to evaluate the efficacy of DKI. In this study, in vivo DKI experiments were performed in normal Sprague-Dawley rats of 3 different ages: postnatal days 13, 31 and 120 (N=6 for each group). Regional analysis was then performed for 4 white matter (WM) and 3 gray matter (GM) structures. Diffusivity and kurtosis estimates derived from DKI were shown to be highly sensitive to the developmental changes in these chosen structures. Conventional diffusion tensor imaging (DTI) parameters were also computed using monoexponential model, yielding reduced sensitivity and directional specificity in monitoring the brain maturation changes. These results demonstrated that, by measuring directionally specific diffusivity and kurtosis, DKI offers a more comprehensive and sensitive detection of tissue microstructural changes. Such imaging advance can provide a better MR diffusion characterization of neural tissues, both WM and GM, in normal, developmental and pathological states.

  View details for DOI 10.1016/j.neuroimage.2008.12.018

  View details for PubMedID 19150655

• Proton magnetic resonance spectroscopy revealed choline reduction in the visual cortex in an experimental model of chronic glaucoma. Experimental eye research Chan, K. C., So, K. F., Wu, E. X. 2009; 88 (1): 65-70

  Abstract

  Glaucoma is a neurodegenerative disease of the visual system. While elevated intraocular pressure is considered to be a major risk factor, the primary cause and pathogenesis of this disease are still unclear. This study aims to employ in vivo proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the metabolic changes in the visual cortex in a rat model of chronic glaucoma. Five Sprague-Dawley female rats were prepared to induce ocular hypertension unilaterally in the right eye by photocoagulating the episcleral and limbal veins using an argon laser. Single voxel (1)H MRS was performed on each side of the visual cortex 6 weeks after laser treatment. Relative to the creatine level, the choline level was found to be significantly lower in the left glaucomatous visual cortex than the right control visual cortex in all animals. In addition, a marginally significant increase in glutamate level was observed in the glaucomatous visual cortex. No apparent difference was observed between contralateral sides of the visual cortex in T1-weighted or T2-weighted imaging. The results of this study showed that glaucoma is accompanied with alterations in the metabolism of choline-containing compounds in the visual cortex contralateral to the glaucomatous rat eye. These potentially associated the pathophysiological mechanisms of glaucoma with the dysfunction of the cholinergic system in the visual pathway. (1)H MRS is a potential tool for studying the metabolic changes in glaucoma in vivo in normally appearing brain structures, and may possess direct clinical applications for humans. Measurement of the Cho:Cr reduction in the visual cortex may be a noninvasive biomarker for this disease.

  View details for DOI 10.1016/j.exer.2008.10.002

  View details for PubMedID 18992243

• Measurement of common carotid artery lumen dynamics during the cardiac cycle using magnetic resonance TrueFISP cine imaging. Journal of magnetic resonance imaging : JMRI Chow, T. Y., Cheung, J. S., Wu, Y., Guo, H., Chan, K. C., Hui, E. S., Wu, E. X. 2008; 28 (6): 1527-32

  Abstract

  To demonstrate magnetic resonance (MR) measurements of vascular lumen dynamics in common carotid arteries by using true fast imaging with steady-state precession (TrueFISP) cine imaging with an aim to provide additional physiologic information on the vessels.The left and right common carotid arteries were studied in normal young men (N = 6; age = 21-24 years; body weight = 130-175 lbs) using electrocardiogram (ECG)-triggered TrueFISP cine imaging at 20 frames per cardiac cycle. Lumen area waveforms were characterized with specific time and amplitude ratios. Distension values were quantified.Distension values were measured at 25.92 +/- 2.58% and 27.58 +/- 4.44% for the left and right common carotid arteries, respectively. These findings are consistent with those previously documented using ultrasound imaging in a similar age group. Consistent lumen area waveform characteristics were found among the subjects studied.These findings demonstrate for the first time that the use of TrueFISP cine imaging is a robust, rapid technique for quantifying carotid lumen area dynamics and distension, which may be valuable in characterizing and diagnosing cardiovascular diseases.

  View details for DOI 10.1002/jmri.21527

  View details for PubMedID 19025960

• GD-DTPA enhanced MRI of ocular transport in a rat model of chronic glaucoma. Experimental eye research Chan, K. C., Fu, Q. L., Guo, H., So, K. F., Wu, E. X. 2008; 87 (4): 334-41

  Abstract

  Glaucoma is a neurodegenerative disease of the visual system characterized by the elevation of intraocular pressure. While this elevated pressure is related to an increased resistance to the outflow of aqueous humor from the eye, their impacts to the etiology and pathogenesis of the disease are not fully understood. This study aims to employ in vivo Gd-DTPA enhanced magnetic resonance imaging to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. An experimental ocular hypertension model was induced in adult rats using an argon laser to photocoagulate the episcleral and limbal veins on the surface of the eyeball. The enhancements of the MRI signal intensity in the anterior chamber and vitreous body were measured as a function of time following systemic administration of Gd-DTPA solution at 3 mmol/kg. Results showed a progressive T1-weighted signal increase in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the glaucomatous chamber components, which may implicate the cascades of neurodegenerative processes in the retina and the optic nerve.

  View details for DOI 10.1016/j.exer.2008.06.015

  View details for PubMedID 18639546