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Use of computational fluid dynamics for 3D fiber tract visualization on human high-thickness histological slices: histological mesh tractography

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Understanding the intricate three-dimensional relationship between fiber bundles and subcortical nuclei is not a simple task. It is of paramount importance in neurosciences, especially in the field of functional neurosurgery. The current methods for in vivo and post mortem fiber tract visualization have shortcomings and contributions to the field are welcome. Several tracts were chosen to implement a new technique to help visualization of white matter tracts, using high-thickness histology and dark field images. Our study describes the use of computational fluid dynamic simulations for visualization of 3D fiber tracts segmented from dark field microscopy in high-thickness histological slices (histological mesh tractography). A post mortem human brain was MRI scanned prior to skull extraction, histologically processed and serially cut at 430 µm thickness as previously described by our group. High-resolution dark field images were used to segment the outlines of the structures. These outlines served as basis for the construction of a 3D structured mesh, were a Finite Volume Method (FVM) simulation of water flow was performed to generate streamlines representing the geometry. The simulations were accomplished by an open source computer fluid dynamics software. The resulting simulation rendered a realistic 3D impression of the segmented anterior commissure, the left anterior limb of the internal capsule, the left uncinate fascicle, and the dentato-rubral tracts. The results are in line with clinical findings, diffusion MR imaging and anatomical dissection methods.
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Brain Structure and Function (2021) 226:323–333
Use ofcomputational fluid dynamics for3D fiber tract visualization
onhuman high‑thickness histological slices: histological mesh
EduardoJoaquimLopesAlho1,2,3 · ErichT.Fono2· AnaTerezaDiLorenzoAlho3· JózsefNagy4· HelmutHeinsen1,3
Received: 29 October 2019 / Accepted: 24 November 2020 / Published online: 3 January 2021
© Springer-Verlag GmbH Germany, part of Springer Nature 2021
Understanding the intricate three-dimensional relationship between fiber bundles and subcortical nuclei is not a simple
task. It is of paramount importance in neurosciences, especially in the field of functional neurosurgery. The current methods
for invivo and post mortem fiber tract visualization have shortcomings and contributions to the field are welcome. Several
tracts were chosen to implement a new technique to help visualization of white matter tracts, using high-thickness histology
and dark field images. Our study describes the use of computational fluid dynamic simulations for visualization of 3D fiber
tracts segmented from dark field microscopy in high-thickness histological slices (histological mesh tractography). A post
mortem human brain was MRI scanned prior to skull extraction, histologically processed and serially cut at 430µm thickness
as previously described by our group. High-resolution dark field images were used to segment the outlines of the structures.
These outlines served as basis for the construction of a 3D structured mesh, were a Finite Volume Method (FVM) simulation
of water flow was performed to generate streamlines representing the geometry. The simulations were accomplished by an
open source computer fluid dynamics software. The resulting simulation rendered a realistic 3D impression of the segmented
anterior commissure, the left anterior limb of the internal capsule, the left uncinate fascicle, and the dentato-rubral tracts.
The results are in line with clinical findings, diffusion MR imaging and anatomical dissection methods.
Keywords Tractography· White matter· Histology· Human brain· Dentato-rubral tract· Diffusion tensor imaging
Advances in neuroimaging and its rapid widespread for
multiple fields of the neurosciences require a better under-
standing of the intricate three-dimensional (3D) relation-
ship between white matter tracts, cortical grey matter and
subcortical nuclei. In the field of functional neurosurgery,
the refinement of stereotactic method based in individual-
ized neuroimaging studies have made possible to aim inter-
ventions at diminutive deep-seated nuclei or fiber tracts, as
therapeutic targets for successful treatment of various neu-
ropsychiatric disorders. Nowadays, it is of paramount impor-
tance, not only the origin and the aim point of a specific fiber
tract, but the topographic localization of the actual pathway
among other deep brain structures. In the field of deep brain
stimulation (DBS), newly designed electrodes with direc-
tional and multiple-contact leads highlight the possibility
of target compounds instead of a single one. The concept of
targeting trajectories instead of a single nucleus has upturned
the effects of DBS, increasing the complexity of stereotactic
interventions (Dos Santos Ghilardi etal. 2018). Such innova-
tions require detailed understanding and accurate maps of
the 3D microscopic neuroanatomy.
Current white matter tract visualization methods include
invivo and post mortem techniques. Diffusion tensor imag-
ing (DTI) and tractography, introduced in the early 1990s
(Pierpaoli etal. 1996; Mori etal. 1999), allow invivo
* Eduardo Joaquim Lopes Alho
1 Morphological Brain Research Unit, Department
ofPsychiatry, University ofWürzburg, Würzburg, Germany
2 Division ofFunctional Neurosurgery, Department
ofNeurology, University ofSão Paulo Medical School, Rua
Dr. Ovidio Pires de Campos, 785, SãoPaulo01060-970,
3 Laboratory forMedical Investigations 44, Department
ofRadiology, São Paulo Medical School, SãoPaulo, Brazil
4 Eulerian-Solutions E.U, Linz, Austria
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... An alternative approach involves lipophilic dyes that act as post mortem tracers. While these techniques have been used mainly to validate fiber configurations locally within a histological section, it is also possible to apply 3D reconstruction to the sections and use them to follow fiber bundles through the brain (Mollink et al., 2016;Alho et al., 2021). ...
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The use of neurophysiological monitoring during surgical procedures has developed extensively in the past decade to become an important adjunctive technique to assist surgical teams and add more safety to surgical treatment approaches. In stereotactic and functional neurosurgery, the outcome results are intimately related to the target definition and adverse effect avoidance. In stereotactic-guided procedures, as in movement disorder surgery, the targets are deep seated in the brain. Therefore, the neurophysiological monitoring aims to avoid damage to the nervous tissue and participates in the decision-making of target localization, improving outcome. Stereotactic localization relies on perioperative imaging, frame-based patient’s head registration, and individual anatomical landmarks. Stereotactic-mounted probes are used for neuronal activity recording (microelectrode recording and local field potential), impedance monitoring, or controlled electrical stimulation to complement final target definition and correct positioning of the deep brain stimulation electrodes. This chapter covers the use of neurophysiological techniques used for movement disorder surgery.
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Background Major depression (MD) and obsessive-compulsive disorder (OCD) are psychiatric diseases with a huge impact on individual well-being. Despite optimal treatment regiments a subgroup of patients remains treatment resistant and stereotactic surgery (stereotactic lesion surgery, SLS or Deep Brain Stimulation, DBS) might be an option. Recent research has described four networks related to MD and OCD (affect, reward, cognitive control, default network) but only on a cortical and the adjacent sub-cortical level. Despite the enormous impact of comparative neuroanatomy, animal science and stereotactic approaches a holistic theory of subcortical and cortical network interactions is elusive. Because of the dominant hierarchical rank of the neocortex, corticofugal approaches have been used to identify connections in subcortical anatomy without anatomical priors and in part confusing results. We here propose a different corticopetal approach by identifying subcortical networks and search for neocortical convergences thereby following the principle of phylogenetic and ontogenetic network development. Material and Methods This work used a diffusion tensor imaging data from a normative cohort (Human Connectome Project, HCP; n=200) to describe eight subcortical fiber projection pathways (PPs) from subthalamic nucleus (STN), substantia nigra (SNR), red nucleus (RN), ventral tegmental area (VTA), ventrolateral thalamus (VLT) and mediodorsal thalamus (MDT) in a normative space (MNI). Subcortical and cortical convergences were described including an assignment of the specific pathways to MD/OCD-related networks. Volumes of activated tissue for different stereotactic stimulation sites and procedures were simulated to understand the role of the distinct networks, with respect to symptoms and treatment of OCD and MD. Results The detailed course of eight subcortical PPs (stnPP, snrPP, rnPP, vlATR, vlATRc, mdATR, mdATRc, vtaPP/slMFB) were described together with their subcortical and cortical convergences. The anterior limb of the internal capsule can be subdivided with respect to network occurrences in ventral-dorsal and medio-lateral gradients. Simulation of stereotactic procedures for OCD and MD showed dominant involvement of mdATR/mdATRc (affect network) and vtaPP/slMFB (reward network). Discussion Corticofugal search strategies for the evaluation of stereotactic approaches without anatomical priors often lead to confusing results which do not allow for a clear assignment of a procedure to an involved network. According to our simulation of stereotactic procedures in the treatment of OCD and MD, most of the target regions directly involve the reward (and affect) networks, while side-effects can in part be explained with a co-modulation of the control network. Conclusion The here proposed corticopetal approach of a hierarchical description of 8 subcortical PPs with subcortical and cortical convergences represents a new systematics of networks found in all different evolutionary and distinct parts of the human brain. Keywords Anterior limb of internal capsule; DBS; Stereotactic Lesion Surgery; Depression; MD; OCD; Projection Pathways; Hyperdirect Pathway; Midbrain; Neocortex; Functional Networks; Prefrontal Cortex
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Characterizing precisely the microstructure of axons, their density, size and myelination is of interest for the neuroscientific community, for example to help maximize the outcome of studies on white matter (WM) pathologies of the spinal cord (SC). The existence of a comprehensive and structured database of axonal measurements in healthy and disease models could help the validation of results obtained by different researchers. The purpose of this article is to provide such a database of healthy SC WM, to discuss the potential sources of variability and to suggest avenues for robust and accurate quantification of axon morphometry based on novel acquisition and processing techniques. The article is organized in three sections. The first section reviews morphometric results across species according to range of densities and counts of myelinated axons, axon diameter and myelin thickness, and characteristics of unmyelinated axons in different regions. The second section discusses the sources of variability across studies, such as age, sex, spinal pathways, spinal levels, statistical power and terminology in regard to tracts and protocols. The third section presents new techniques and perspectives that could benefit histology studies. For example, coherent anti-stokes Raman spectroscopy (CARS) imaging can provide sub-micrometric resolution without the need for fixation and staining, while slide scanners and stitching algorithms can provide full cross-sectional area of SC. In combination with these acquisition techniques, automatic segmentation algorithms for delineating axons and myelin sheath can help provide large-scale statistics on axon morphometry.
Micro-architectural characteristics of white matter can be inferred through analysis of diffusion-weighted magnetic resonance imaging (dMRI). The diffusion-dependent signal can be analyzed through several methods, with the tensor model being the most frequently used due to its straightforward interpretation and low requirements for acquisition parameters. While valuable information can be gained from the tensor-derived metrics in regions of homogeneous tissue organization, this model does not provide reliable microstructural information at crossing fiber regions, which are pervasive throughout human white matter. Several multiple fiber models have been proposed that seem to overcome the limitations of the tensor, with few providing per-bundle dMRI-derived metrics. However, biological interpretations of such metrics are limited by the lack of histological confirmation. To this end, we developed a straightforward biological validation framework. Unilateral retinal ischemia was induced in ten rats, which resulted in axonal (Wallerian) degeneration of the corresponding optic nerve, while the contralateral was left intact; the intact and injured axonal populations meet at the optic chiasm as they cross the midline, generating a fiber crossing region in which each population has different diffusion properties. Five rats served as controls. High-resolution ex vivo dMRI was acquired five weeks after experimental procedures. We correlated and compared histology to per-bundle descriptors derived from three methodologies for dMRI analysis (constrained spherical deconvolution and two multi-tensor representations). We found a tight correlation between axonal density (as evaluated through automatic segmentation of histological sections) with per-bundle apparent fiber density and fractional anisotropy (derived from dMRI). The multi-fiber methods explored were able to correctly identify the damaged fiber populations in a region of fiber crossings (chiasm). Our results provide validation of metrics that bring substantial and clinically useful information about white-matter tissue at crossing fiber regions. Our proposed framework is useful to validate other current and future dMRI methods.
Multi-compartment tissue modeling using diffusion magnetic resonance imaging has proven valuable in the brain, offering novel indices sensitive to the tissue microstructural environment in vivo on clinical MRI scanners. However, application, characterization, and validation of these models in the spinal cord remain relatively under-studied. In this study, we apply a diffusion "signal" model (diffusion tensor imaging, DTI) and two commonly implemented "microstructural" models (neurite orientation dispersion and density imaging, NODDI; spherical mean technique, SMT) in the human cervical spinal cord of twenty-one healthy controls. We first provide normative values of DTI, SMT, and NODDI indices in a number of white matter ascending and descending pathways, as well as various gray matter regions. We then aim to validate the sensitivity and specificity of these diffusion-derived contrasts by relating these measures to indices of the tissue microenvironment provided by a histological template. We find that DTI indices are sensitive to a number of microstructural features, but lack specificity. The microstructural models also show sensitivity to a number of microstructure features; however, they do not capture the specific microstructural features explicitly modelled. Although often regarded as a simple extension of the brain in the central nervous system, it may be necessary to re-envision, or specifically adapt, diffusion microstructural models for application to the human spinal cord with clinically feasible acquisitions - specifically, adjusting, adapting, and re-validating the modeling as it relates to both theory (i.e. relevant biology, assumptions, and signal regimes) and parameter estimation (for example challenges of acquisition, artifacts, and processing).