A novel algorithm for multiplicative speckle noise reduction in ex vivo human brain OCT images.

Optical coherence tomography (OCT) images of ex vivo human brain tissue are corrupted by multiplicative speckle noise that degrades the contrast to noise ratio (CNR) of microstructural compartments. This work proposes a novel algorithm to reduce noise corruption in OCT images that minimizes the penalized negative log likelihood of gamma distributed speckle noise. The proposed method is formulated as a majorize-minimize problem that reduces to solving an iterative regularized least squares optimization. We demonstrate the usefulness of the proposed method by removing speckle in simulated data, phantom data and real OCT images of human brain tissue. We compare the proposed method with state of the art filtering and non-local means based denoising methods. We demonstrate that our approach removes speckle accurately, improves CNR between different tissue types and better preserves small features and edges in human brain tissue.

The trigeminal system: The meningovascular complex- A review.

Supratentorial sensory perception, including pain, is subserved by the trigeminal nerve, in particular, by the branches of its ophthalmic division, which provide an extensive innervation of the dura mater and of the major brain blood vessels. In addition, contrary to previous assumptions, studies on awake patients during surgery have demonstrated that the mechanical stimulation of the pia mater and small cerebral vessels can also produce pain. The trigeminovascular system, located at the interface between the nervous and vascular systems, is therefore perfectly positioned to detect sensory inputs and influence blood flow regulation. Despite the fact that it remains only partially understood, the trigeminovascular system is most probably involved in several pathologies, including very frequent ones such as migraine, or other severe conditions, such as subarachnoid haemorrhage. The incomplete knowledge about the exact roles of the trigeminal system in headache, blood flow regulation, blood barrier permeability and trigemino-cardiac reflex warrants for an increased investigation of the anatomy and physiology of the trigeminal system. This translational review aims at presenting comprehensive information about the dural and brain afferents of the trigeminovascular system, in order to improve the understanding of trigeminal cranial sensory perception and to spark a new field of exploration for headache and other brain diseases.

Insight into the fundamental trade-offs of diffusion MRI from polarization-sensitive optical coherence tomography in ex vivo human brain.

In the first study comparing high angular resolution diffusion MRI (dMRI) in the human brain to axonal orientation measurements from polarization-sensitive optical coherence tomography (PSOCT), we compare the accuracy of orientation estimates from various dMRI sampling schemes and reconstruction methods. We find that, if the reconstruction approach is chosen carefully, single-shell dMRI data can yield the same accuracy as multi-shell data, and only moderately lower accuracy than a full Cartesian-grid sampling scheme. Our results suggest that current dMRI reconstruction approaches do not benefit substantially from ultra-high b-values or from very large numbers of diffusion-encoding directions. We also show that accuracy remains stable across dMRI voxel sizes of 1 â€‹mm or smaller but degrades at 2 â€‹mm, particularly in areas of complex white-matter architecture. We also show that, as the spatial resolution is reduced, axonal configurations in a dMRI voxel can no longer be modeled as a small set of distinct axon populations, violating an assumption that is sometimes made by dMRI reconstruction techniques. Our findings have implications for in vivo studies and illustrate the value of PSOCT as a source of ground-truth measurements of white-matter organization that does not suffer from the distortions typical of histological techniques.

as-PSOCT: Volumetric microscopic imaging of human brain architecture and connectivity.

Polarization sensitive optical coherence tomography (PSOCT) with serial sectioning has enabled the investigation of 3D structures in mouse and human brain tissue samples. By using intrinsic optical properties of back-scattering and birefringence, PSOCT reliably images cytoarchitecture, myeloarchitecture and fiber orientations. In this study, we developed a fully automatic serial sectioning polarization sensitive optical coherence tomography (as-PSOCT) system to enable volumetric reconstruction of human brain samples with unprecedented sample size and resolution. The 3.5 µm in-plane resolution and 50 µm through-plane voxel size allow inspection of cortical layers that are a single-cell in width, as well as small crossing fibers. We show the abilities of as-PSOCT in quantifying layer thicknesses of the cerebellar cortex and creating microscopic tractography of intricate fiber networks in the subcortical nuclei and internal capsule regions, all based on volumetric reconstructions. as-PSOCT provides a viable tool for studying quantitative cytoarchitecture and myeloarchitecture and mapping connectivity with microscopic resolution in the human brain.

En face speckle reduction in optical coherence microscopy by frequency compounding.

We report the use of frequency compounding to significantly reduce speckle noise in optical coherence microscopy, more specifically on the en face images. This method relies on the fact that the speckle patterns recorded from different wavelengths simultaneously are independent; hence their summation yields significant reduction in noise, with only a single acquisition. The results of our experiments with microbeads show that the narrow confocal parameter, due to a high numerical aperture objective, restricts the axial resolution loss that would otherwise theoretically broaden linearly with the number of optical frequency bands used. This speckle reduction scheme preserves the lateral resolution since it is performed on individual A-scans. Finally, we apply this technique to images of fixed human brain tissue, showing significant improvements in contrast-to-noise ratio with only moderate loss of axial resolution, in an effort to improve automatic three-dimensional detection of cells and fibers in the cortex.

Polarization sensitive optical coherence microscopy for brain imaging.

Optical coherence tomography (OCT) and optical coherence microscopy (OCM) have demonstrated the ability to investigate cyto- and myelo-architecture in the brain. Polarization-sensitive OCT provides sensitivity to additional contrast mechanisms, specifically the birefringence of myelination and, therefore, is advantageous for investigating white matter fiber tracts. In this Letter, we developed a polarization-sensitive optical coherence microscope (PS-OCM) with a 3.5 µm axial and 1.3 µm transverse resolution to investigate fiber organization and orientation at a finer scale than previously demonstrated with PS-OCT. In a reconstructed mouse brain section, we showed that at the focal depths of 20-70 µm, the PS-OCM reliably identifies the neuronal fibers and quantifies the in-plane orientation.

Multi-modal robust inverse-consistent linear registration.

Registration performance can significantly deteriorate when image regions do not comply with model assumptions. Robust estimation improves registration accuracy by reducing or ignoring the contribution of voxels with large intensity differences, but existing approaches are limited to monomodal registration. In this work, we propose a robust and inverse-consistent technique for cross-modal, affine image registration. The algorithm is derived from a contextual framework of image registration. The key idea is to use a modality invariant representation of images based on local entropy estimation, and to incorporate a heteroskedastic noise model. This noise model allows us to draw the analogy to iteratively reweighted least squares estimation and to leverage existing weighting functions to account for differences in local information content in multimodal registration. Furthermore, we use the nonparametric windows density estimator to reliably calculate entropy of small image patches. Finally, we derive the Gauss-Newton update and show that it is equivalent to the efficient second-order minimization for the fully symmetric registration approach. We illustrate excellent performance of the proposed methods on datasets containing outliers for alignment of brain tumor, full head, and histology images.

MRI parcellation of ex vivo medial temporal lobe.

Recent advancements in radio frequency coils, field strength and sophisticated pulse sequences have propelled modern brain mapping and have made validation to biological standards - histology and pathology - possible. The medial temporal lobe has long been established as a pivotal brain region for connectivity, function and unique structure in the human brain, and reveals disconnection in mild Alzheimer's disease. Specific brain mapping of mesocortical areas affected with neurofibrillary tangle pathology early in disease progression provides not only an accurate description for location of these areas but also supplies spherical coordinates that allow comparison between other ex vivo cases and larger in vivo datasets. We have identified several cytoarchitectonic features in the medial temporal lobe with high resolution ex vivo MRI, including gray matter structures such as the entorhinal layer II 'islands', perirhinal layer II-III columns, presubicular 'clouds', granule cell layer of the dentate gyrus as well as lamina of the hippocampus. Localization of Brodmann areas 28 and 35 (entorhinal and perirhinal, respectively) demonstrates MRI based area boundaries validated with multiple methods and histological stains. Based on our findings, both myelin and Nissl staining relate to contrast in ex vivo MRI. Precise brain mapping serves to create modern atlases for cortical areas, allowing accurate localization with important applications to detecting early disease processes.

Blockface histology with optical coherence tomography: a comparison with Nissl staining.

Spectral domain optical coherence tomography (SD-OCT) is a high resolution imaging technique that generates excellent contrast based on intrinsic optical properties of the tissue, such as neurons and fibers. The SD-OCT data acquisition is performed directly on the tissue block, diminishing the need for cutting, mounting and staining. We utilized SD-OCT to visualize the laminar structure of the isocortex and compared cortical cytoarchitecture with the gold standard Nissl staining, both qualitatively and quantitatively. In histological processing, distortions routinely affect registration to the blockface image and prevent accurate 3D reconstruction of regions of tissue. We compared blockface registration to SD-OCT and Nissl, respectively, and found that SD-OCT-blockface registration was significantly more accurate than Nissl-blockface registration. Two independent observers manually labeled cortical laminae (e.g. III, IV and V) in SD-OCT images and Nissl stained sections. Our results show that OCT images exhibit sufficient contrast in the cortex to reliably differentiate the cortical layers. Furthermore, the modalities were compared with regard to cortical laminar organization and showed good agreement. Taken together, these SD-OCT results suggest that SD-OCT contains information comparable to standard histological stains such as Nissl in terms of distinguishing cortical layers and architectonic areas. Given these data, we propose that SD-OCT can be used to reliably generate 3D reconstructions of multiple cubic centimeters of cortex that can be used to accurately and semi-automatically perform standard histological analyses.

Age-related decline in oligodendrogenesis retards white matter repair in mice.

BACKGROUND AND PURPOSE: Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury. METHODS: A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month-old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells to sublethal 7-day CoCl2 treatment to induce chemical hypoxic stress. RESULTS: Baseline myelin density in the corpus callosum was similar in 2-month and 8-month-old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in cyclic AMP response element-binding protein signaling may be involved because activating cyclic AMP response element-binding protein with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of oligodendrocyte precursor cells, alleviated myelin loss, and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of oligodendrocyte precursor cells. CONCLUSIONS: An age-related decline in cyclic AMP response element-binding protein-mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate cyclic AMP response element-binding protein signaling provide a potential therapeutic approach for treating white matter injury in aging brains.

Quantitative optical coherence microscopy of neuron morphology in human entorhinal cortex.

Introduction: The size and shape of neurons are important features indicating aging and the pathology of neurodegenerative diseases. Despite the significant advances of optical microscopy, quantitative analysis of the neuronal features in the human brain remains largely incomplete. Traditional histology on thin slices bears tremendous distortions in three-dimensional reconstruction, the magnitude of which are often greater than the structure of interest. Recently development of tissue clearing techniques enable the whole brain to be analyzed in small animals; however, the application in the human remains challenging. Methods: In this study, we present a label-free quantitative optical coherence microscopy (OCM) technique to obtain the morphological parameters of neurons in human entorhinal cortex (EC). OCM uses the intrinsic back-scattering property of tissue to identify individual neurons in 3D. The area, length, width, and orientation of individual neurons are quantified and compared between layer II and III in EC. Results: The high-resolution mapping of neuron size, shape, and orientation shows significant differences between layer II and III neurons in EC. The results are validated by standard Nissl staining of the same samples. Discussion: The quantitative OCM technique in our study offers a new solution to analyze variety of neurons and their organizations in the human brain, which opens new insights in advancing our understanding of neurodegenerative diseases.

Quantitative imaging of three-dimensional fiber orientation in the human brain via two illumination angles using polarization-sensitive optical coherence tomography.

The accurate measurement of three-dimensional (3D) fiber orientation in the brain is crucial for reconstructing fiber pathways and studying their involvement in neurological diseases. Optical imaging methods such as polarization-sensitive optical coherence tomography (PS-OCT) provide important tools to directly quantify fiber orientation at micrometer resolution. However, brain imaging based on the optic axis by PS-OCT so far has been limited to two-dimensional in-plane orientation, preventing the comprehensive study of connectivity in 3D. In this work, we present a novel method to obtain the 3D fiber orientation in full angular space with only two illumination angles. We measure the optic axis orientation and the apparent birefringence by PS-OCT from a normal and a 15 deg tilted illumination, and then apply a computational method yielding the 3D optic axis orientation and true birefringence. We verify that our method accurately recovers a large range of through-plane orientations from -85 deg to 85 deg with a high angular precision. We further present 3D fiber orientation maps of entire coronal sections of human cerebrum and brainstem with 10 µm in-plane resolution, revealing unprecedented details of fiber configurations. We envision that further development of our method will open a promising avenue towards large-scale 3D fiber axis mapping in the human brain and other complex fibrous tissues at microscopic level.

Multi-Scale Label-Free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy.

The study of aging and neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction. Here, the authors describe an integrated serial sectioning polarization-sensitive optical coherence tomography (PSOCT) and two photon microscopy (2PM) system to provide label-free multi-contrast imaging of intact brain structures, including scattering, birefringence, and autofluorescence of human brain tissue. The authors demonstrate high-throughput reconstruction of 4 × 4 × 2cm3 sample blocks and simple registration between PSOCT and 2PM images that enable comprehensive analysis of myelin content, vascular structure, and cellular information. The high-resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical properties on the same sample, revealing the densely packed fibers, capillaries, and lipofuscin-filled cell bodies in the cortex and white matter. It is  shown that the imaging system enables quantitative characterization of various pathological features in aging process, including myelin degradation, lipofuscin accumulation, and microvascular changes, which opens up numerous opportunities in the study of neurodegenerative diseases in the future.

Multi-Scale Label-free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy.

The study of neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction of the human brain. The development of a multi-scale and volumetric human brain imaging technique that can measure intact brain structure would be a major technical advance. Here, we describe the development of integrated serial sectioning Polarization Sensitive Optical Coherence Tomography (PSOCT) and Two Photon Microscopy (2PM) to provide label-free multi-contrast imaging, including scattering, birefringence and autofluorescence of human brain tissue. We demonstrate that high-throughput reconstruction of 4×4×2cm3 sample blocks and simple registration of PSOCT and 2PM images enable comprehensive analysis of myelin content, vascular structure, and cellular information. We show that 2µm in-plane resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical property maps on the same sample, revealing the sophisticated capillary networks and lipofuscin filled cell bodies across the cortical layers. Our method is applicable to the study of a variety of pathological processes, including demyelination, cell loss, and microvascular changes in neurodegenerative diseases such as Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE).

A cellular resolution atlas of Broca's area.

Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)-referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with a digital stereological approach on the 3D reconstruction at cellular resolution from a custom-made inverted confocal light-sheet fluorescence microscope (LSFM). Mesoscale optical coherence tomography enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system. The outcome is an integrated high-resolution cellular census of Broca's area in a human postmortem specimen, within a whole-brain reference space atlas.

Refractive-index matching enhanced polarization sensitive optical coherence tomography quantification in human brain tissue.

The importance of polarization-sensitive optical coherence tomography (PS-OCT) has been increasingly recognized in human brain imaging. Despite the recent progress of PS-OCT in revealing white matter architecture and orientation, quantification of fine-scale fiber tracts in the human brain cortex has been a challenging problem, due to a low birefringence in the gray matter. In this study, we investigated the effect of refractive index matching by 2,2'-thiodiethanol (TDE) immersion on the improvement of PS-OCT measurements in ex vivo human brain tissue. We show that we can obtain fiber orientation maps of U-fibers that underlie sulci, as well as cortical fibers in the gray matter, including radial fibers in gyri and distinct layers of fibers exhibiting laminar organization. Further analysis shows that index matching reduces the noise in axis orientation measurements by 56% and 39%, in white and gray matter, respectively. Index matching also enables precise measurements of apparent birefringence, which was underestimated in the white matter by 82% but overestimated in the gray matter by 16% prior to TDE immersion. Mathematical simulations show that the improvements are primarily attributed to the reduction in the tissue scattering coefficient, leading to an enhanced signal-to-noise ratio in deeper tissue regions, which could not be achieved by conventional noise reduction methods.

Scalable mapping of myelin and neuron density in the human brain with micrometer resolution.

Optical coherence tomography (OCT) is an emerging 3D imaging technique that allows quantification of intrinsic optical properties such as scattering coefficient and back-scattering coefficient, and has proved useful in distinguishing delicate microstructures in the human brain. The origins of scattering in brain tissues are contributed by the myelin content, neuron size and density primarily; however, no quantitative relationships between them have been reported, which hampers the use of OCT in fundamental studies of architectonic areas in the human brain and the pathological evaluations of diseases. Here, we built a generalized linear model based on Mie scattering theory that quantitatively links tissue scattering to myelin content and neuron density in the human brain. We report a strong linear relationship between scattering coefficient and the myelin content that is retained across different regions of the brain. Neuronal cell body turns out to be a secondary contribution to the overall scattering. The optical property of OCT provides a label-free solution for quantifying volumetric myelin content and neuron cells in the human brain.

Quantitative and histologically validated measures of the entorhinal subfields in ex vivo MRI.

Neuroimaging studies have routinely used hippocampal volume as a measure of Alzheimer's disease severity, but hippocampal changes occur too late in the disease process for potential therapies to be effective. The entorhinal cortex is one of the first cortical areas affected by Alzheimer's disease; its neurons are especially vulnerable to neurofibrillary tangles. Entorhinal atrophy also relates to the conversion from non-clinical to clinical Alzheimer's disease. In neuroimaging, the human entorhinal cortex has so far mostly been considered in its entirety or divided into a medial and a lateral region. Cytoarchitectonic differences provide the opportunity for subfield parcellation. We investigated the entorhinal cortex on a subfield-specific level-at a critical time point of Alzheimer's disease progression. While MRI allows multidimensional quantitative measurements, only histology provides enough accuracy to determine subfield boundaries-the pre-requisite for quantitative measurements within the entorhinal cortex. This study used histological data to validate ultra-high-resolution 7 Tesla ex vivo MRI and create entorhinal subfield parcellations in a total of 10 pre-clinical Alzheimer's disease and normal control cases. Using ex vivo MRI, eight entorhinal subfields (olfactory, rostral, medial intermediate, intermediate, lateral rostral, lateral caudal, caudal, and caudal limiting) were characterized for cortical thickness, volume, and pial surface area. Our data indicated no influence of sex, or Braak and Braak staging on volume, cortical thickness, or pial surface area. The volume and pial surface area for mean whole entorhinal cortex were 1131 ± 55.72 mm3 and 429 ± 22.6 mm2 (mean ± SEM), respectively. The subfield volume percentages relative to the entire entorhinal cortex were olfactory: 18.73 ± 1.82%, rostral: 14.06 ± 0.63%, lateral rostral: 14.81 ± 1.22%, medial intermediate: 6.72 ± 0.72%, intermediate: 23.36 ± 1.85%, lateral caudal: 5.42 ± 0.33%, caudal: 10.99 ± 1.02%, and caudal limiting: 5.91 ± 0.40% (all mean ± SEM). Olfactory and intermediate subfield revealed the most extensive intra-individual variability (cross-subject variance) in volume and pial surface area. This study provides validated measures. It maps individuality and demonstrates human variability in the entorhinal cortex, providing a baseline for approaches in individualized medicine. Taken together, this study serves as a ground-truth validation study for future in vivo comparisons and treatments.

Volumetric Characterization of Microvasculature in Ex Vivo Human Brain Samples By Serial Sectioning Optical Coherence Tomography.

OBJECTIVE: Serial sectioning optical coherence tomography (OCT) enables accurate volumetric reconstruction of several cubic centimeters of human brain samples. We aimed to identify anatomical features of the ex vivo human brain, such as intraparenchymal blood vessels and axonal fiber bundles, from the OCT data in 3D, using intrinsic optical contrast. METHODS: We developed an automatic processing pipeline to enable characterization of the intraparenchymal microvascular network in human brain samples. RESULTS: We demonstrated the automatic extraction of the vessels down to a 20 µm in diameter using a filtering strategy followed by a graphing representation and characterization of the geometrical properties of microvascular network in 3D. We also showed the ability to extend this processing strategy to extract axonal fiber bundles from the volumetric OCT image. CONCLUSION: This method provides a viable tool for quantitative characterization of volumetric microvascular network as well as the axonal bundle properties in normal and pathological tissues of the ex vivo human brain.

Uncertainty-Aware Annotation Protocol to Evaluate Deformable Registration Algorithms.

Landmark correspondences are a widely used type of gold standard in image registration. However, the manual placement of corresponding points is subject to high inter-user variability in the chosen annotated locations and in the interpretation of visual ambiguities. In this paper, we introduce a principled strategy for the construction of a gold standard in deformable registration. Our framework: (i) iteratively suggests the most informative location to annotate next, taking into account its redundancy with previous annotations; (ii) extends traditional pointwise annotations by accounting for the spatial uncertainty of each annotation, which can either be directly specified by the user, or aggregated from pointwise annotations from multiple experts; and (iii) naturally provides a new strategy for the evaluation of deformable registration algorithms. Our approach is validated on four different registration tasks. The experimental results show the efficacy of suggesting annotations according to their informativeness, and an improved capacity to assess the quality of the outputs of registration algorithms. In addition, our approach yields, from sparse annotations only, a dense visualization of the errors made by a registration method. The source code of our approach supporting both 2D and 3D data is publicly available at https://github.com/LoicPeter/evaluation-deformable-registration.