Publications by authors named "David A Rudko"

13 Publications

  • Page 1 of 1

Quantitation of Tissue Resection Using a Brain Tumor Model and 7-T Magnetic Resonance Imaging Technology.

World Neurosurg 2021 Apr 5;148:e326-e339. Epub 2021 Jan 5.

Neurosurgical Simulation and Artificial Intelligence Learning Centre, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Background: Animal brain tumor models can be useful educational tools for the training of neurosurgical residents in risk-free environments. Magnetic resonance imaging (MRI) technologies have not used these models to quantitate tumor, normal gray and white matter, and total tissue removal during complex neurosurgical procedures. This pilot study was carried out as a proof of concept to show the feasibility of using brain tumor models combined with 7-T MRI technology to quantitatively assess tissue removal during subpial tumor resection.

Methods: Seven ex vivo calf brain hemispheres were used to develop the 7-T MRI segmentation methodology. Three brains were used to quantitate brain tissue removal using 7-T MRI segmentation methodology. Alginate artificial brain tumor was created in 4 calf brains to assess the ability of 7-T MRI segmentation methodology to quantitate tumor and gray and white matter along with total tissue volumes removal during a subpial tumor resection procedure.

Results: Quantitative studies showed a correlation between removed brain tissue weights and volumes determined from segmented 7-T MRIs. Analysis of baseline and postresection alginate brain tumor segmented 7-T MRIs allowed quantification of tumor and gray and white matter along with total tissue volumes removed and detection of alterations in surrounding gray and white matter.

Conclusions: This pilot study showed that the use of animal tumor models in combination with 7-T MRI technology provides an opportunity to increase the granularity of data obtained from operative procedures and to improve the assessment and training of learners.
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http://dx.doi.org/10.1016/j.wneu.2020.12.141DOI Listing
April 2021

Creating a Comprehensive Research Platform for Surgical Technique and Operative Outcome in Primary Brain Tumor Neurosurgery.

World Neurosurg 2020 Dec 3;144:e62-e71. Epub 2020 Aug 3.

Neurosurgical Simulation and Artificial Intelligence Learning Centre, McGill University, Montreal, Quebec, Canada.

Background: The operative environment poses many challenges to studying the relationship between surgical acts and patient outcomes in intracranial oncological neurosurgery. We sought to develop a framework in which neurosurgical performance and extent of resection could be precisely quantified in a controlled setting.

Methods: The stiffness of an alginate hydrogel-based tumor was modified with differing concentrations of the cross-linking agent calcium sulfate until biomechanical properties similar to those of human primary brain tumors measured at resection were achieved. The artificial tumor was subsequently incorporated into an ex-vivo animal brain as a final model. Magnetic resonance imaging enhancement and ultraviolet fluorescence was achieved by incorporating gadolinium and fluorescein solution, respectively. Video recordings from the operative microscope, ceiling cameras, and instrument-mounted fiducial markers within a surgical suite environment captured operative performance.

Results: A total of 24 rheometer measurements were conducted on alginate hydrogels containing 10-, 11-, and 12-mM concentrations of calcium sulfate. Sixty-eight stiffness measurements were conducted on eight patient tumor samples. No differences were found between the alginate and brain tumor stiffness values [Kruskal-Wallis χ(4) = 9.187; P = 0.057]. Tumor was identified using ultraviolet fluorescence and ultrasonography. The volume and location of the resected white and gray matter and residual tumor could be quantified in 0.003-mm increments using a 7T magnetic resonance imaging coil. Ultrasonic aspirator and bipolar electrocautery movement data were successfully transformed into performance metrics.

Conclusion: The developed framework can offer clinicians, learners, and researchers the ability to perform operative rehearsal, teaching, and studies involving brain tumor surgery in a controlled laboratory environment and represents a crucial step in the understanding and training of expertise in neurosurgery.
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http://dx.doi.org/10.1016/j.wneu.2020.07.209DOI Listing
December 2020

PET Imaging of Perceptual Learning-Induced Changes in the Aged Rodent Cholinergic System.

Front Neurosci 2019 21;13:1438. Epub 2020 Jan 21.

Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

The cholinergic system enhances attention and gates plasticity, making it a major regulator of adult learning. With aging, however, progressive degeneration of the cholinergic system impairs both the acquisition of new skills and functional recovery following neurological injury. Although cognitive training and perceptual learning have been shown to enhance auditory cortical processing, their specific impact on the cholinergic system remains unknown. Here we used [F]FEOBV, a positron emission tomography (PET) radioligand that selectively binds to the vesicular acetylcholine transporter (VAChT), as a proxy to assess whether training on a perceptual task results in increased cholinergic neurotransmission. We show for the first time that perceptual learning is associated with region-specific changes in cholinergic neurotransmission, as detected by [F]FEOBV PET imaging and corroborated with immunohistochemistry.
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http://dx.doi.org/10.3389/fnins.2019.01438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985428PMC
January 2020

MRI Based Brain-Specific 3D-Printed Model Aligned to Stereotactic Space for Registering Histology to MRI.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:802-805

Studies that seek to predict the brain microstructure based on MRI require precise alignment of processed brain histology slices to the corresponding 3D MRI data. However, achieving such alignment is a challenging problem, due to tissue distortions and the different contrasts seen in MRI and the processed tissue. Here we present a pipeline for aligning a histology volume to the MRI data of the tissue and to a stereotaxic brain atlas. To this end, we segment the volume of the brain from ex-vivo MRI data, align the MRI data obtained in the native space to an MRI stereotaxic template and create a 3D printed model (a mold or cradle) that precisely fits the brain. The pipeline then makes it possible to create grooves in the 3D model, for guiding blades for cutting slabs of tissue. Placing the brain in the brain-specific 3D printed model aligns the tissue to the MRI data by default. Aligning the MRI data to an MRI stereotaxic template makes it possible to section histology slices parallel to the standard stereotaxic axes of the atlas. This facilitates comparisons to other MRI contrasts and to images of processed tissue aligned to the standard space, while maintaining the high-resolution of the tissue images along the standard stereotaxic plane. Guiding the positioning of the grooves according to species-specific anatomical information from the co-registered atlas facilitates region-specific histology. The pipeline we introduce can be used to create brain-specific sectioning models for a variety of species, including humans, primates, and rodents. To demonstrate the generalizability of the pipeline across species, we show models generated for macaques and rats.
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http://dx.doi.org/10.1109/EMBC.2018.8512346DOI Listing
July 2018

An Open Resource for Non-human Primate Imaging.

Neuron 2018 10 27;100(1):61-74.e2. Epub 2018 Sep 27.

Centre for Social Learning and Cognitive Evolution, School of Biology, University of St. Andrews, St. Andrews, UK.

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.
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http://dx.doi.org/10.1016/j.neuron.2018.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231397PMC
October 2018

MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis.

Neurology 2017 Aug 19;89(7):714-721. Epub 2017 Jul 19.

From the Department of Neurology and Neurosurgery (J.M., D.A.R., K.N., D.L.A., S.N.), Montreal Neurological Hospital and Institute, McGill University, Canada; Cleveland Clinic (K.N.), OH; Rutgers-New Jersey Medical School (S.C., D.C.), Newark, NJ; and Case Western Reserve University (L.W.), Cleveland, OH. L.W. is currently with the University of Connecticut, School of Medicine, Farmington.

Objective: To identify gadolinium-enhancing lesions affecting the cortex of patients with early multiple sclerosis (MS) and to describe the frequency and evolution of these lesions.

Methods: We performed a retrospective, observational, longitudinal analysis of MRI scans collected as part of the Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3T MRI Endpoints (BECOME) study. Seventy-five patients with early-stage MS were scanned monthly, over a period of 12-24 months, using 3T MRI after administration of triple-dose gadolinium. A total of 1,188 scans were included in the analysis. A total of 139 were selected using an image pipeline algorithm that integrated the image information from cortical gray matter masks and gadolinium-enhancing lesion masks. These scans were evaluated to identify gadolinium-enhancing lesions affecting the cortex.

Results: The total number of gadolinium-enhancing lesions was 2,044. The number of gadolinium-enhancing lesions affecting the cortex was 120 (6%), 95% of which were leukocortical. The number of patients who showed gadolinium-enhancing lesions affecting the cortex was 27 (36%). The number of gadolinium-enhancing lesions affecting the cortex at baseline was 25 (21%) and the number of new lesions that developed in follow-up scans was 49 (41%). The number of persistent lesions was 46 (38%).

Conclusions: The presence of enhancing lesions affecting the cortex and adjacent white matter, although transient and not frequent, suggests that at least some cortical lesions are related to blood-brain barrier disruption. Our data support the concept that there may be an acute inflammatory phase in the development of leukocortical MS lesions.

Clinicaltrialsgov Identifier: NCT00176592.
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http://dx.doi.org/10.1212/WNL.0000000000004227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562966PMC
August 2017

Preferential susceptibility of limbic cortices to microstructural damage in temporal lobe epilepsy: A quantitative T1 mapping study.

Neuroimage 2018 11 3;182:294-303. Epub 2017 Jun 3.

Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada. Electronic address:

The majority of MRI studies in temporal lobe epilepsy (TLE) have utilized morphometry to map widespread cortical alterations. Morphological markers, such as cortical thickness or grey matter density, reflect combinations of biological events largely driven by overall cortical geometry rather than intracortical tissue properties. Because of its sensitivity to intracortical myelin, quantitative measurement of longitudinal relaxation time (qT) provides and an in vivo proxy for cortical microstructure. Here, we mapped the regional distribution of qT in a consecutive cohort of 24 TLE patients and 20 healthy controls. Compared to controls, patients presented with a strictly ipsilateral distribution of qT increases in temporopolar, parahippocampal and orbitofrontal cortices. Supervised statistical learning applied to qT maps could lateralize the seizure focus in 92% of patients. Intracortical profiling of qT along streamlines perpendicular to the cortical mantle revealed marked effects in upper levels that tapered off at the white matter interface. Findings remained robust after correction for cortical thickness and interface blurring, suggesting independence from previously reported morphological anomalies in this disorder. Mapping of qT along hippocampal subfield surfaces revealed marked increases in anterior portions of the ipsilateral CA1-3 and DG that were also robust against correction for atrophy. Notably, in operated patients, qualitative histopathological analysis of myelin stains in resected hippocampal specimens confirmed disrupted internal architecture and fiber organization. Both hippocampal and neocortical qT anomalies were more severe in patients with early disease onset. Finally, analysis of resting-state connectivity from regions of qT increases revealed altered intrinsic functional network embedding in patients, particularly to prefrontal networks. Analysis of qT suggests a preferential susceptibility of ipsilateral limbic cortices to microstructural damage, possibly related to disrupted myeloarchitecture. These alterations may reflect atypical neurodevelopment and affect the integrity of fronto-limbic functional networks.
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http://dx.doi.org/10.1016/j.neuroimage.2017.06.002DOI Listing
November 2018

Delineation of cortical pathology in multiple sclerosis using multi-surface magnetization transfer ratio imaging.

Neuroimage Clin 2016 13;12:858-868. Epub 2016 Oct 13.

McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

The purpose of our study was to evaluate the utility of measurements of cortical surface magnetization transfer ratio (csMTR) on the inner, mid and outer cortical boundaries as clinically accessible biomarkers of cortical gray matter pathology in multiple sclerosis (MS). Twenty-five MS patients and 12 matched controls were recruited from the MS Clinic of the Montreal Neurological Institute. Anatomical and magnetization transfer ratio (MTR) images were acquired using 3 Tesla MRI at baseline and two-year time-points. MTR maps were smoothed along meshes representing the inner, mid and outer neocortical boundaries. To evaluate csMTR reductions suggestive of sub-pial demyelination in MS patients, a mixed model analysis was carried out at both the individual vertex level and in anatomically parcellated brain regions. Our results demonstrate that focal areas of csMTR reduction are most prevalent along the outer cortical surface in the superior temporal and posterior cingulate cortices, as well as in the cuneus and precentral gyrus. Additionally, age regression analysis identified that reductions of csMTR in MS patients increase with age but appear to hit a plateau in the outer caudal anterior cingulate, as well as in the precentral and postcentral cortex. After correction for the naturally occurring gradient in cortical MTR, the difference in csMTR between the inner and outer cortex in focal areas in the brains of MS patients correlated with clinical disability. Overall, our findings support multi-surface analysis of csMTR as a sensitive marker of cortical sub-pial abnormality indicative of demyelination in MS patients.
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http://dx.doi.org/10.1016/j.nicl.2016.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107650PMC
November 2017

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.

J Neurotrauma 2016 12 1;33(24):2202-2216. Epub 2016 Jun 1.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO treatment. Finally, AC105 did not result in higher Mg levels in CSF than with the use of standard MgSO. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.
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http://dx.doi.org/10.1089/neu.2016.4439DOI Listing
December 2016

Multiple sclerosis: improved identification of disease-relevant changes in gray and white matter by using susceptibility-based MR imaging.

Radiology 2014 Sep 14;272(3):851-64. Epub 2014 May 14.

From the Department of Physics (D.A.R., R.S.M.), Center for Functional and Metabolic Mapping, Robarts Research Institute (D.A.R., I.S., J.S.G., R.S.M.), and Department of Neurology, University Hospital (M.K.), University of Western Ontario, 1151 Richmond St North, London, ON, Canada N6A 5B7.

Purpose: To evaluate the potential of quantitative susceptibility (QS) and R2* mapping as surrogate biomarkers of clinically relevant, age-adjusted demyelination and iron deposition in multiple sclerosis (MS).

Materials And Methods: All study participants gave written informed consent, and the study was approved by the institutional review board. Quantitative maps of the magnetic resonance imaging susceptibility parameters (R2* and QS) were computed for 25 patients with either clinically isolated syndrome (CIS) or relapsing-remitting MS, as well as for 15 age- and sex-matched control subjects imaged at 7 T. The candidate MR imaging biomarkers were correlated with Extended Disability Status Scale (EDSS), time since CIS diagnosis, time since MS diagnosis, and age.

Results: QS maps aided identification of significant, voxel-level increases in iron deposition in subcortical gray matter (GM) of patients with MS compared with control subjects. These voxel-level increases were not observed on R2* maps. Region-of-interest analysis of mean R2* and QS in subcortical GM demonstrated that R2* (R ≥ 0.39, P < .01) and QS (R ≥ 0.44, P < .01) were strongly correlated with EDSS. In white matter (WM), the volume of total WM damage (defined by a z score of less than -2.0 criterion, indicating demyelination) on QS maps correlated significantly with EDSS (R = 0.46, P = .02). Voxelwise QS also supported a significant contribution of age to demyelination in patients with MS, suggesting that age-adjusted clinical scores may provide more robust measures of MS disease severity compared with non-age-adjusted scores.

Conclusion: Using QS and R2* mapping, evidence of both significant increases in iron deposition in subcortical GM and myelin degeneration along the WM skeleton of patients with MS was identified. Both effects correlated strongly with EDSS.
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http://dx.doi.org/10.1148/radiol.14132475DOI Listing
September 2014

Inter-echo variance as a weighting factor for multi-channel combination in multi-echo acquisition for local frequency shift mapping.

Magn Reson Med 2015 Apr 18;73(4):1654-61. Epub 2014 Apr 18.

Imaging Research Laboratories, Robarts Research Institute, University of Western Ontario, London, Canada.

Purpose: To develop and evaluate a local frequency shift (LFS) mapping method specifically designed for multi-echo acquisitions and multi-channel receive coils.

Methods: The proposed method uses the pixel-by-pixel inter-echo variance (IEV) as a weighting factor during channel-combination. Five healthy volunteers were scanned at 7 T. The IEV-weighted method was quantitatively compared to established (adaptive and Hermitian product) channel-combination methods with respect to IEV of LFS over the entire brain.

Results: In all experiments, the IEV-weighted method generated LFS maps free of artifacts caused by unwrapping errors. Based on measurements of the inter-echo frequency variance throughout the whole brain, the IEV-weighted method produced the lowest variation and the best contrast at the edge of the brain.

Conclusion: The primary finding of the present study is that accurate LFS maps are achievable if the data from each channel is processed independently prior to combination followed by a weighted combination using IEV as the weighting term. The software is freely available to the scientific community.
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http://dx.doi.org/10.1002/mrm.25247DOI Listing
April 2015

Origins of R2* orientation dependence in gray and white matter.

Proc Natl Acad Sci U S A 2014 Jan 27;111(1):E159-67. Epub 2013 Dec 27.

Department of Physics and Astronomy, University of Western Ontario, London, ON, Canada N6A 3K7.

Estimates of the apparent transverse relaxation rate (R2*) can be used to quantify important properties of biological tissue. Surprisingly, the mechanism of R2* dependence on tissue orientation is not well understood. The primary goal of this paper was to characterize orientation dependence of R2* in gray and white matter and relate it to independent measurements of two other susceptibility based parameters: the local Larmor frequency shift (fL) and quantitative volume magnetic susceptibility (Δχ). Through this comparative analysis we calculated scaling relations quantifying R2' (reversible contribution to the transverse relaxation rate from local field inhomogeneities) in a voxel given measurements of the local Larmor frequency shift. R2' is a measure of both perturber geometry and density and is related to tissue microstructure. Additionally, two methods (the Generalized Lorentzian model and iterative dipole inversion) for calculating Δχ were compared in gray and white matter. The value of Δχ derived from fitting the Generalized Lorentzian model was then connected to the observed R2* orientation dependence using image-registered optical density measurements from histochemical staining. Our results demonstrate that the R2* and fL of white and cortical gray matter are well described by a sinusoidal dependence on the orientation of the tissue and a linear dependence on the volume fraction of myelin in the tissue. In deep brain gray matter structures, where there is no obvious symmetry axis, R2* and fL have no orientation dependence but retain a linear dependence on tissue iron concentration and hence Δχ.
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http://dx.doi.org/10.1073/pnas.1306516111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890825PMC
January 2014

In vivo normative atlas of the hippocampal subfields using multi-echo susceptibility imaging at 7 Tesla.

Hum Brain Mapp 2014 Aug 13;35(8):3588-601. Epub 2013 Dec 13.

Imaging Research Laboratories, Robarts Research Institute, Western University, London, Ontario, Canada; Biomedical Engineering, Western University, London, Ontario, Canada.

Objectives: To generate a high-resolution atlas of the hippocampal subfields using images acquired from 7 T, multi-echo, gradient-echo MRI for the evaluation of epilepsy and neurodegenerative disorders as well as investigating R2* (apparent transverse relaxation rate) and quantitative volume magnetic susceptibility (QS) of the subfields.

Experimental Design: Healthy control subjects (n=17) were scanned at 7 T using a multi-echo gradient-echo sequence and susceptibility-weighted magnitude images, R2* and QS maps were reconstructed. We defined a hippocampal subfield labeling protocol for the magnitude image produced from the average of all echoes and assessed reproducibility through volume and shape metrics. A group-wise diffeomorphic registration procedure was used to generate an average atlas of the subfields for the whole subject cohort. The quantitative MRI maps and subfield labels were then warped to the average atlas space and used to measure mean values of R2* and QS characterizing each subfield.

Principal Observations: We were able to reliably label hippocampal subfields on the multi-echo susceptibility images. The group-averaged atlas accurately aligns these structures to produce a high-resolution depiction of the subfields, allowing assessment of both quantitative susceptibility and R2* across subjects. Our analysis of variance demonstrates that there are more apparent differences between the subfields on these quantitative maps than the normalized magnitude images.

Conclusion: We constructed a high-resolution atlas of the hippocampal subfields for use in voxel-based studies and demonstrated in vivo quantification of susceptibility and R2* in the subfields. This work is the first in vivo quantification of susceptibility values within the hippocampal subfields at 7 T.
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http://dx.doi.org/10.1002/hbm.22423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869628PMC
August 2014