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Chase Figley

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University of Huddersfield

Mehmet Akif KILIC

Sağlık Bilimleri Üniversitesi

Shiraz University Of Medical Sciences

Tehran University of Medical Sciences

Universidad Central de Venezuela

Sampath Chandra Prasad Rao

Manipal Academy of Higher Education

Eskisehir Osmangazi University, Turkey

University of Toronto

University of Southern California

Richard J Harvey

The University of New South Wales

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Papers by Chase Figley

Altered voxel-based and surface-based morphometry in inflammatory bowel disease

Brain Research Bulletin

Vascular comorbidity is associated with decreased cognitive functioning in inflammatory bowel disease

Scientific Reports

Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and card... more Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and cardiovascular disease are often co-morbid, yet it remains unknown whether vascular comorbidity confers a risk for decreased cognitive functioning, as observed in other populations. Participants with IBD were recruited from a longitudinal study of immune-mediated disease. Participants were administered a standardized neuropsychological test protocol, evaluating information processing speed, verbal learning and memory, visual learning and memory, and verbal fluency/executive function. Cognitive test scores were standardized using local regression-based norms, adjusting for age, sex, and education. Vascular risk was calculated using a modified Framingham Risk Score (FRS). We tested the association between FRS and cognitive test scores using a quantile regression model, adjusting for IBD type. Of 84 IBD participants, 54 had ulcerative colitis and 30 had Crohn’s disease; mean (SD) age was 53.36 ...

Spatial normalization of multiple sclerosis brain MRI data depends on analysis method and software package

Magnetic Resonance Imaging

Background: Spatially normalizing brain MRI data to a template is commonly performed to facilitat... more Background: Spatially normalizing brain MRI data to a template is commonly performed to facilitate comparisons between individuals or groups. However, the presence of multiple sclerosis (MS) lesions and other MSrelated brain pathologies may compromise the performance of automated spatial normalization procedures. We therefore aimed to systematically compare five commonly used spatial normalization methods for brain MRIincluding linear (affine), and nonlinear MRIStudio (LDDMM), FSL (FNIRT), ANTs (SyN), and SPM (CAT12) algorithms -to evaluate their performance in the presence of MS-related pathologies. Methods: 3 Tesla MRI images (T1-weighted and T2-FLAIR) were obtained for 20 participants with MS from an ongoing cohort study (used to assess a real dataset) and 1 healthy control participant (used to create a simulated lesion dataset). Both raw and lesion-filled versions of each participant's T1-weighted brain images were warped to the Montreal Neurological Institute (MNI) template using all five normalization approaches for the real dataset, and the same procedure was then repeated using the simulated lesion dataset (i.e., total of 400 spatial normalizations). As an additional quality-assurance check, the resulting deformations were also applied to the corresponding lesion masks to evaluate how each processing pipeline handled focal white matter lesions. For each normalization approach, intersubject variability (across normalized T1-weighted images) was quantified using both mutual information (MI) and

Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Frontiers in Neuroscience

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used... more Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at le...

Performance of Regression-Based Norms for Cognitive Functioning of Persons With Multiple Sclerosis in an Independent Sample

Frontiers in Neurology, 2021

Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsy... more Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsychological tests requires the use of normative data. Traditionally, normative data have been reported for discrete categories such as age. More recently continuous norms have been developed using multivariable regression equations that account for multiple demographic factors. Regression-based norms have been developed for use in the Canadian population for tests included in the MACFIMS and BICAMS test batteries. Establishing the generalizability of these norms is essential for application in clinical and research settings.Objectives: We aimed to (i) test the performance of previously published Canadian regression-based norms in an independently collected sample of Canadian healthy controls; (ii) compare the ability of Canadian and non-Canadian regression-based norms to discriminate between healthy controls and persons with MS; and (iii) develop regression-based norms for several cogniti...

Anxiety and depression affect performance on the symbol digit modalities test over time in MS and other immune disorders

Multiple Sclerosis Journal, 2020

Background: Longitudinal studies assessing depression and anxiety effects on cognition in multipl... more Background: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. Objective: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID). Methods: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models—estimating between-person and within-person effects. Results: Participants with MS performed worse on the SDMT than participants in the DEP/ANX co...

Comparison of Multi-echo Gradient and Spin Echo (GRASE) and Fast Spin Echo (FSE) MRI Sequences for T1w/T2w Ratio Mapping

Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury

Frontiers in Neurology, 2021

Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) ove... more Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the “one-treatment fits all” approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex “-omics” data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can ...

Higher Framingham Risk Scores are associated with greater loss of brain volume over time in multiple sclerosis

Multiple Sclerosis and Related Disorders, 2021

BACKGROUND Few studies have evaluated the association between comorbidities associated with incre... more BACKGROUND Few studies have evaluated the association between comorbidities associated with increased vascular risk and brain volume changes in multiple sclerosis (MS). To date, findings have not been consistent with respect to which comorbidities are associated with lower brain volumes or whether comorbidities associated with increased vascular risk are associated with greater brain volume loss over time. OBJECTIVES We aimed to evaluate the association between the Framingham Risk Score (FRS) which evaluates vascular risk and normalized whole brain volume in MS. METHODS We included 98 participants with MS who underwent two brain MRIs two years apart, from which whole brain volumes were calculated. Each participant reported their comorbidities and medications taken. Blood pressure, height and weight were recorded and we calculated the FRS. We tested the association between the FRS at baseline and brain volume at the second time point using quantile regression adjusting for baseline normalized brain volume, age, gender and use of disease-modifying therapy. RESULTS As the FRS increased, brain volume was lower, both at enrollment (β= -0.24; 95%CI: -0.42, -0.04) and at follow-up (-0.27; 95%CI: -0.45, -0.08). After further adjustment for age, gender, and use of disease modifying therapy, higher FRS remained associated with lower brain volume at follow-up at the 90th percentile of brain volume (β= -2.22; 95%CI: -3.40, -1.04) but not at the 10th or 50th percentiles. CONCLUSION Higher FRS were associated with lower brain volumes in persons with MS at baseline, and with brain volume loss over time. This effect was most pronounced for persons with higher brain volumes at baseline, which suggests that prevention, detection and effective management of comorbidities associated with vascular risk in people with MS is particularly important early in the disease course.

Whole-brain dynamics in aging: disruptions in functional connectivity and the role of the rich club

Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fM... more Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fMRI studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent (BOLD) signals to analyze resting-state fMRI data from 620 subjects divided into two groups (‘middle-age group’ (n=310); age range, 50-65 years vs. ‘older group’ (n=310); age range, 66-91 years). Applying the Intrinsic-Ignition Framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functio...

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population

Mechanisms of Ageing and Development, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Magnetic Resonance Imaging Biomarkers of Brain Connectivity in Predicting Outcome after Mild Traumatic Brain Injury: A Systematic Review

Journal of Neurotrauma, 2020

There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain conn... more There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain connectivity from resting-state functional (rs-fMRI) and diffusion tensor imaging (DTI) to aid in the management of patients with mild traumatic brain injury (mTBI). To determine whether early MRI biomarkers of brain connectivity are useful in predicting outcome after mTBI, we conducted a systematic review using the following inclusion criteria: (1) patients aged>16 years with mTBI, (2) MRI performed during the first month post-injury, (3) outcome measure available, (4) control group, and (5) original paper published in a peer-reviewed journal. Of the 1351 citations identified, 14 studies met inclusion criteria (5 rs-fMRI and 10 DTI; 680 mTBI patients vs 436 controls) including those where MRI was performed from <12 hours to 1 month post-injury. The most common clinical outcome measure used in these studies was symptom burden using the Rivermead Post-Concussion Questionnaire. The most frequently studied brain connectivity MRI biomarkers were global functional connectivity, default-mode network, and fractional anisotropy. Despite the scant evidence and considerable methodological heterogeneity observed among studies, we conclude that brain connectivity MRI biomarkers obtained within one month of injury may be potentially useful in predicting outcome in mTBI. Further longitudinal studies are needed to evaluate the effect of mTBI on MRI-based brain connectivity biomarkers and examine how incorporation of these tests can inform the clinical care of individual mTBI patients.

$Research paper thumbnail of Comparisons between multi-component myelin water fraction, T1w/T2w ratio, and diffusion tensor imaging measures in healthy human brain structures$

Comparisons between multi-component myelin water fraction, T1w/T2w ratio, and diffusion tensor imaging measures in healthy human brain structures

Scientific Reports, 2019

Various MRI techniques, including myelin water imaging, T1w/T2w ratio mapping and diffusion-based... more Various MRI techniques, including myelin water imaging, T1w/T2w ratio mapping and diffusion-based imaging can be used to characterize tissue microstructure. However, surprisingly few studies have examined the degree to which these MRI measures are related within and between various brain regions. Therefore, whole-brain MRI scans were acquired from 31 neurologically-healthy participants to empirically measure and compare myelin water fraction (MWF), T1w/T2w ratio, fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) in 25 bilateral (10 grey matter; 15 white matter) regions-of-interest (ROIs). Except for RD vs. T1w/T2w, MD vs. T1w/T2w, moderately significant to highly significant correlations (p < 0.001) were found between each of the other measures across all 25 brain structures [T1w/T2w vs. MWF (Pearson r = 0.33, Spearman ρ = 0.31), FA vs. MWF (r = 0.73, ρ = 0.75), FA vs. T1w/T2w (r = 0.25, ρ = 0.22), MD vs. AD (r = 0.57, ρ = 0.58)...

Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence

Frontiers in Neuroscience, 2018

$Research paper thumbnail of {"__content__"=>"Effect of echo time and T-weighting on GRASE-based Tw/Tw ratio measurements at 3T.", "sub"=>[{"__content__"=>"2"}, {"__content__"=>"1"}, {"__content__"=>"2"}]}$

{"__content__"=>"Effect of echo time and T-weighting on GRASE-based Tw/Tw ratio measurements at 3T.", "sub"=>[{"__content__"=>"2"}, {"__content__"=>"1"}, {"__content__"=>"2"}]}

Magnetic resonance imaging, 2018

Tissue contrast can be enhanced by dividing T-weighted (Tw) images by T-weighted (Tw) images to m... more Tissue contrast can be enhanced by dividing T-weighted (Tw) images by T-weighted (Tw) images to map the so-called Tw/Tw ratio, which has become an increasingly popular technique for quantifying brain tissue changes associated with neurodevelopment, aging, and a variety of neurodegenerative diseases. However, although it is self-evident that Tw/Tw ratios increase with the amount of T-weighting in the Tw image - which is determined by the echo time (TE), all else being equal - longer TEs also reduce the signal-to-noise ratio (SNR) of the Tw images, and it is not clear how these SNR characteristics affect the reliability of Tw/Tw measurements. Therefore, the current study systematically investigated how different amounts of T-weighting affected Tw/Tw measurements in order to determine whether there is an optimal amount of T-weighting. Tw images were acquired from 10 neurologically healthy adults using a 3D turbo field echo (TFE) sequence, and a series of T-weighted images were extracte...

Diabetes and anxiety adversely affect cognition in multiple sclerosis

Multiple Sclerosis and Related Disorders, 2019

To determine whether comorbid diabetes and hypertension are associated with cognition in multiple... more To determine whether comorbid diabetes and hypertension are associated with cognition in multiple sclerosis (MS) after accounting for psychiatric comorbidities. Methods: Participants completed a structured psychiatric interview, the Hospital Anxiety and Depression Scale (HADS), a comorbidity questionnaire, and cognitive testing including the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and verbal fluency. Test scores were converted to age-, sex-and education-adjusted z-scores. We evaluated associations between diabetes and hypertension and the four cognitive z-scores using a multivariate linear model, adjusting for comorbid depression and anxiety disorders, psychotropic medications, disease-modifying therapies, smoking status and body mass index. Results: Of 111 participants, most were women (82.9%) with relapsing remitting MS (83.5%), of mean (SD) age 49.6 (12.7) years. Comorbidity was common; 22.7% participants had hypertension, 10.8% had diabetes, 9.9% had current major depression, and 9.9% had current anxiety disorders. Mean (SD) z-scores were: SDMT -0.66 (1.15), CVLT-II -0.43 (1.32), BVMT-R -0.49 (1.07) and fluency -0.59 (0.86). Diabetes (p = 0.02) and anxiety disorder (p = 0.02) were associated with cognitive function overall. Diabetes was associated with lower BVMT-R (β = -1.18, p = 0.0015) and fluency (β = -0.63, p = 0.037) z-scores. Anxiety was associated with lower SDMT (β = -1.07, p = 0.0074) z-scores. Elevated anxiety symptoms (HADS-A ≥ 11) were associated with lower z-scores on the SDMT and CVLT-II. Conclusion: Comorbidities, including diabetes and anxiety, are associated with cognitive dysfunction in MS. Their presence may contribute to the heterogeneous pattern of impairments seen across individuals and they may represent targets for improved management of cognitive symptoms.

Probabilistic White Matter Atlases of Human Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Visual and Visuospatial Networks

Frontiers in Human Neuroscience, 2017

Background: Despite the popularity of functional connectivity analyses and the well-known topolog... more Background: Despite the popularity of functional connectivity analyses and the well-known topology of several intrinsic cortical networks, relatively little is known about the white matter regions (i.e., structural connectivity) underlying these networks. In the current study, we have therefore performed fMRI-guided diffusion tensor imaging (DTI) tractography to create probabilistic white matter atlases for eight previously identified functional brain networks, including the Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Primary Visual, Higher Visual and Visuospatial Networks. Methods: Whole-brain diffusion imaging data were acquired from a cohort of 32 healthy volunteers, and were warped to the ICBM template using a two-stage, highdimensional, non-linear spatial normalization procedure. Deterministic tractography, with fractional anisotropy (FA) ≥0.15 and deviation angle <50 • , was then performed using the Fiber Association by Continuous Tracking (FACT) algorithm, and a multi-ROI approach to identify tracts of interest. Regions-of-interest (ROIs) for each of the eight networks were taken from a pre-existing atlas of functionally defined regions to explore all ROI-to-ROI connections within each network, and all resulting streamlines were saved as binary masks to create probabilistic atlases (across participants) for tracts between each ROI-to-ROI pair. Results: The resulting functionally-defined white matter atlases (i.e., for each tract and each network as a whole) were saved as NIFTI images in stereotaxic ICBM coordinates, and have been added to the UManitoba-JHU Functionally-Defined Human White Matter Atlas ().

A Method for Whole Brain Ex Vivo Magnetic Resonance Imaging with Minimal Susceptibility Artifacts

Frontiers in Neurology, 2016

Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pat... more Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pathologies and assessing other anatomical features (e.g., tissue volume, microstructure, and white matter connectivity) in postmortem, ex vivo human brains. However, when brains are removed from the skull and cerebrospinal fluid (i.e., their normal in vivo magnetic environment), air bubbles and air-tissue interfaces typically cause magnetic susceptibility artifacts that severely degrade the quality of ex vivo MRI data. In this report, we describe a relatively simple and cost-effective experimental setup for acquiring artifact-free ex vivo brain images using a clinical MRI system with standard hardware. In particular, we outline the necessary steps, from collecting an ex vivo human brain to the MRI scanner setup, and have also described changing the formalin (as might be necessary in longitudinal postmortem studies). Finally, we share some representative ex vivo MRI images that have been acquired using the proposed setup in order to demonstrate the efficacy of this approach. We hope that this protocol will provide both clinicians and researchers with a straight-forward and cost-effective solution for acquiring ex vivo MRI data from whole postmortem human brains.

Effects of Body Mass Index and Body Fat Percent on Default Mode, Executive Control, and Salience Network Structure and Function

Frontiers in Neuroscience, 2016

Probabilistic atlases of default mode, executive control and salience network white matter tracts: an fMRI-guided diffusion tensor imaging and tractography study

Frontiers in Human Neuroscience, 2015

The Review Editor Pew-Thian Yap declares that, despite being affiliated with the same institution... more The Review Editor Pew-Thian Yap declares that, despite being affiliated with the same institution as the Associate Editor Charlotte A. Boettiger, the review process was handled objectively. The Review Editor Kenichi Oishi declares that, despite being affiliated with the same institution as the Author Susan Courtney, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Altered voxel-based and surface-based morphometry in inflammatory bowel disease

Brain Research Bulletin

Vascular comorbidity is associated with decreased cognitive functioning in inflammatory bowel disease

Scientific Reports

Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and card... more Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and cardiovascular disease are often co-morbid, yet it remains unknown whether vascular comorbidity confers a risk for decreased cognitive functioning, as observed in other populations. Participants with IBD were recruited from a longitudinal study of immune-mediated disease. Participants were administered a standardized neuropsychological test protocol, evaluating information processing speed, verbal learning and memory, visual learning and memory, and verbal fluency/executive function. Cognitive test scores were standardized using local regression-based norms, adjusting for age, sex, and education. Vascular risk was calculated using a modified Framingham Risk Score (FRS). We tested the association between FRS and cognitive test scores using a quantile regression model, adjusting for IBD type. Of 84 IBD participants, 54 had ulcerative colitis and 30 had Crohn’s disease; mean (SD) age was 53.36 ...

Spatial normalization of multiple sclerosis brain MRI data depends on analysis method and software package

Magnetic Resonance Imaging

Background: Spatially normalizing brain MRI data to a template is commonly performed to facilitat... more Background: Spatially normalizing brain MRI data to a template is commonly performed to facilitate comparisons between individuals or groups. However, the presence of multiple sclerosis (MS) lesions and other MSrelated brain pathologies may compromise the performance of automated spatial normalization procedures. We therefore aimed to systematically compare five commonly used spatial normalization methods for brain MRIincluding linear (affine), and nonlinear MRIStudio (LDDMM), FSL (FNIRT), ANTs (SyN), and SPM (CAT12) algorithms -to evaluate their performance in the presence of MS-related pathologies. Methods: 3 Tesla MRI images (T1-weighted and T2-FLAIR) were obtained for 20 participants with MS from an ongoing cohort study (used to assess a real dataset) and 1 healthy control participant (used to create a simulated lesion dataset). Both raw and lesion-filled versions of each participant's T1-weighted brain images were warped to the Montreal Neurological Institute (MNI) template using all five normalization approaches for the real dataset, and the same procedure was then repeated using the simulated lesion dataset (i.e., total of 400 spatial normalizations). As an additional quality-assurance check, the resulting deformations were also applied to the corresponding lesion masks to evaluate how each processing pipeline handled focal white matter lesions. For each normalization approach, intersubject variability (across normalized T1-weighted images) was quantified using both mutual information (MI) and

Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Frontiers in Neuroscience

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used... more Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at le...

Performance of Regression-Based Norms for Cognitive Functioning of Persons With Multiple Sclerosis in an Independent Sample

Frontiers in Neurology, 2021

Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsy... more Background: Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsychological tests requires the use of normative data. Traditionally, normative data have been reported for discrete categories such as age. More recently continuous norms have been developed using multivariable regression equations that account for multiple demographic factors. Regression-based norms have been developed for use in the Canadian population for tests included in the MACFIMS and BICAMS test batteries. Establishing the generalizability of these norms is essential for application in clinical and research settings.Objectives: We aimed to (i) test the performance of previously published Canadian regression-based norms in an independently collected sample of Canadian healthy controls; (ii) compare the ability of Canadian and non-Canadian regression-based norms to discriminate between healthy controls and persons with MS; and (iii) develop regression-based norms for several cogniti...

Anxiety and depression affect performance on the symbol digit modalities test over time in MS and other immune disorders

Multiple Sclerosis Journal, 2020

Background: Longitudinal studies assessing depression and anxiety effects on cognition in multipl... more Background: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. Objective: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID). Methods: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models—estimating between-person and within-person effects. Results: Participants with MS performed worse on the SDMT than participants in the DEP/ANX co...

Comparison of Multi-echo Gradient and Spin Echo (GRASE) and Fast Spin Echo (FSE) MRI Sequences for T1w/T2w Ratio Mapping

Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury

Frontiers in Neurology, 2021

Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) ove... more Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the “one-treatment fits all” approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex “-omics” data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can ...

Higher Framingham Risk Scores are associated with greater loss of brain volume over time in multiple sclerosis

Multiple Sclerosis and Related Disorders, 2021

BACKGROUND Few studies have evaluated the association between comorbidities associated with incre... more BACKGROUND Few studies have evaluated the association between comorbidities associated with increased vascular risk and brain volume changes in multiple sclerosis (MS). To date, findings have not been consistent with respect to which comorbidities are associated with lower brain volumes or whether comorbidities associated with increased vascular risk are associated with greater brain volume loss over time. OBJECTIVES We aimed to evaluate the association between the Framingham Risk Score (FRS) which evaluates vascular risk and normalized whole brain volume in MS. METHODS We included 98 participants with MS who underwent two brain MRIs two years apart, from which whole brain volumes were calculated. Each participant reported their comorbidities and medications taken. Blood pressure, height and weight were recorded and we calculated the FRS. We tested the association between the FRS at baseline and brain volume at the second time point using quantile regression adjusting for baseline normalized brain volume, age, gender and use of disease-modifying therapy. RESULTS As the FRS increased, brain volume was lower, both at enrollment (β= -0.24; 95%CI: -0.42, -0.04) and at follow-up (-0.27; 95%CI: -0.45, -0.08). After further adjustment for age, gender, and use of disease modifying therapy, higher FRS remained associated with lower brain volume at follow-up at the 90th percentile of brain volume (β= -2.22; 95%CI: -3.40, -1.04) but not at the 10th or 50th percentiles. CONCLUSION Higher FRS were associated with lower brain volumes in persons with MS at baseline, and with brain volume loss over time. This effect was most pronounced for persons with higher brain volumes at baseline, which suggests that prevention, detection and effective management of comorbidities associated with vascular risk in people with MS is particularly important early in the disease course.

Whole-brain dynamics in aging: disruptions in functional connectivity and the role of the rich club

Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fM... more Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state fMRI studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent (BOLD) signals to analyze resting-state fMRI data from 620 subjects divided into two groups (‘middle-age group’ (n=310); age range, 50-65 years vs. ‘older group’ (n=310); age range, 66-91 years). Applying the Intrinsic-Ignition Framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functio...

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population

Mechanisms of Ageing and Development, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Magnetic Resonance Imaging Biomarkers of Brain Connectivity in Predicting Outcome after Mild Traumatic Brain Injury: A Systematic Review

Journal of Neurotrauma, 2020

There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain conn... more There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain connectivity from resting-state functional (rs-fMRI) and diffusion tensor imaging (DTI) to aid in the management of patients with mild traumatic brain injury (mTBI). To determine whether early MRI biomarkers of brain connectivity are useful in predicting outcome after mTBI, we conducted a systematic review using the following inclusion criteria: (1) patients aged>16 years with mTBI, (2) MRI performed during the first month post-injury, (3) outcome measure available, (4) control group, and (5) original paper published in a peer-reviewed journal. Of the 1351 citations identified, 14 studies met inclusion criteria (5 rs-fMRI and 10 DTI; 680 mTBI patients vs 436 controls) including those where MRI was performed from <12 hours to 1 month post-injury. The most common clinical outcome measure used in these studies was symptom burden using the Rivermead Post-Concussion Questionnaire. The most frequently studied brain connectivity MRI biomarkers were global functional connectivity, default-mode network, and fractional anisotropy. Despite the scant evidence and considerable methodological heterogeneity observed among studies, we conclude that brain connectivity MRI biomarkers obtained within one month of injury may be potentially useful in predicting outcome in mTBI. Further longitudinal studies are needed to evaluate the effect of mTBI on MRI-based brain connectivity biomarkers and examine how incorporation of these tests can inform the clinical care of individual mTBI patients.

$Research paper thumbnail of Comparisons between multi-component myelin water fraction, T1w/T2w ratio, and diffusion tensor imaging measures in healthy human brain structures$

Comparisons between multi-component myelin water fraction, T1w/T2w ratio, and diffusion tensor imaging measures in healthy human brain structures

Scientific Reports, 2019

Various MRI techniques, including myelin water imaging, T1w/T2w ratio mapping and diffusion-based... more Various MRI techniques, including myelin water imaging, T1w/T2w ratio mapping and diffusion-based imaging can be used to characterize tissue microstructure. However, surprisingly few studies have examined the degree to which these MRI measures are related within and between various brain regions. Therefore, whole-brain MRI scans were acquired from 31 neurologically-healthy participants to empirically measure and compare myelin water fraction (MWF), T1w/T2w ratio, fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) in 25 bilateral (10 grey matter; 15 white matter) regions-of-interest (ROIs). Except for RD vs. T1w/T2w, MD vs. T1w/T2w, moderately significant to highly significant correlations (p < 0.001) were found between each of the other measures across all 25 brain structures [T1w/T2w vs. MWF (Pearson r = 0.33, Spearman ρ = 0.31), FA vs. MWF (r = 0.73, ρ = 0.75), FA vs. T1w/T2w (r = 0.25, ρ = 0.22), MD vs. AD (r = 0.57, ρ = 0.58)...

Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence

Frontiers in Neuroscience, 2018

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Magnetic resonance imaging, 2018

Tissue contrast can be enhanced by dividing T-weighted (Tw) images by T-weighted (Tw) images to m... more Tissue contrast can be enhanced by dividing T-weighted (Tw) images by T-weighted (Tw) images to map the so-called Tw/Tw ratio, which has become an increasingly popular technique for quantifying brain tissue changes associated with neurodevelopment, aging, and a variety of neurodegenerative diseases. However, although it is self-evident that Tw/Tw ratios increase with the amount of T-weighting in the Tw image - which is determined by the echo time (TE), all else being equal - longer TEs also reduce the signal-to-noise ratio (SNR) of the Tw images, and it is not clear how these SNR characteristics affect the reliability of Tw/Tw measurements. Therefore, the current study systematically investigated how different amounts of T-weighting affected Tw/Tw measurements in order to determine whether there is an optimal amount of T-weighting. Tw images were acquired from 10 neurologically healthy adults using a 3D turbo field echo (TFE) sequence, and a series of T-weighted images were extracte...

Diabetes and anxiety adversely affect cognition in multiple sclerosis

Multiple Sclerosis and Related Disorders, 2019

To determine whether comorbid diabetes and hypertension are associated with cognition in multiple... more To determine whether comorbid diabetes and hypertension are associated with cognition in multiple sclerosis (MS) after accounting for psychiatric comorbidities. Methods: Participants completed a structured psychiatric interview, the Hospital Anxiety and Depression Scale (HADS), a comorbidity questionnaire, and cognitive testing including the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and verbal fluency. Test scores were converted to age-, sex-and education-adjusted z-scores. We evaluated associations between diabetes and hypertension and the four cognitive z-scores using a multivariate linear model, adjusting for comorbid depression and anxiety disorders, psychotropic medications, disease-modifying therapies, smoking status and body mass index. Results: Of 111 participants, most were women (82.9%) with relapsing remitting MS (83.5%), of mean (SD) age 49.6 (12.7) years. Comorbidity was common; 22.7% participants had hypertension, 10.8% had diabetes, 9.9% had current major depression, and 9.9% had current anxiety disorders. Mean (SD) z-scores were: SDMT -0.66 (1.15), CVLT-II -0.43 (1.32), BVMT-R -0.49 (1.07) and fluency -0.59 (0.86). Diabetes (p = 0.02) and anxiety disorder (p = 0.02) were associated with cognitive function overall. Diabetes was associated with lower BVMT-R (β = -1.18, p = 0.0015) and fluency (β = -0.63, p = 0.037) z-scores. Anxiety was associated with lower SDMT (β = -1.07, p = 0.0074) z-scores. Elevated anxiety symptoms (HADS-A ≥ 11) were associated with lower z-scores on the SDMT and CVLT-II. Conclusion: Comorbidities, including diabetes and anxiety, are associated with cognitive dysfunction in MS. Their presence may contribute to the heterogeneous pattern of impairments seen across individuals and they may represent targets for improved management of cognitive symptoms.

Probabilistic White Matter Atlases of Human Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Visual and Visuospatial Networks

Frontiers in Human Neuroscience, 2017

Background: Despite the popularity of functional connectivity analyses and the well-known topolog... more Background: Despite the popularity of functional connectivity analyses and the well-known topology of several intrinsic cortical networks, relatively little is known about the white matter regions (i.e., structural connectivity) underlying these networks. In the current study, we have therefore performed fMRI-guided diffusion tensor imaging (DTI) tractography to create probabilistic white matter atlases for eight previously identified functional brain networks, including the Auditory, Basal Ganglia, Language, Precuneus, Sensorimotor, Primary Visual, Higher Visual and Visuospatial Networks. Methods: Whole-brain diffusion imaging data were acquired from a cohort of 32 healthy volunteers, and were warped to the ICBM template using a two-stage, highdimensional, non-linear spatial normalization procedure. Deterministic tractography, with fractional anisotropy (FA) ≥0.15 and deviation angle <50 • , was then performed using the Fiber Association by Continuous Tracking (FACT) algorithm, and a multi-ROI approach to identify tracts of interest. Regions-of-interest (ROIs) for each of the eight networks were taken from a pre-existing atlas of functionally defined regions to explore all ROI-to-ROI connections within each network, and all resulting streamlines were saved as binary masks to create probabilistic atlases (across participants) for tracts between each ROI-to-ROI pair. Results: The resulting functionally-defined white matter atlases (i.e., for each tract and each network as a whole) were saved as NIFTI images in stereotaxic ICBM coordinates, and have been added to the UManitoba-JHU Functionally-Defined Human White Matter Atlas ().

A Method for Whole Brain Ex Vivo Magnetic Resonance Imaging with Minimal Susceptibility Artifacts

Frontiers in Neurology, 2016

Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pat... more Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pathologies and assessing other anatomical features (e.g., tissue volume, microstructure, and white matter connectivity) in postmortem, ex vivo human brains. However, when brains are removed from the skull and cerebrospinal fluid (i.e., their normal in vivo magnetic environment), air bubbles and air-tissue interfaces typically cause magnetic susceptibility artifacts that severely degrade the quality of ex vivo MRI data. In this report, we describe a relatively simple and cost-effective experimental setup for acquiring artifact-free ex vivo brain images using a clinical MRI system with standard hardware. In particular, we outline the necessary steps, from collecting an ex vivo human brain to the MRI scanner setup, and have also described changing the formalin (as might be necessary in longitudinal postmortem studies). Finally, we share some representative ex vivo MRI images that have been acquired using the proposed setup in order to demonstrate the efficacy of this approach. We hope that this protocol will provide both clinicians and researchers with a straight-forward and cost-effective solution for acquiring ex vivo MRI data from whole postmortem human brains.

Effects of Body Mass Index and Body Fat Percent on Default Mode, Executive Control, and Salience Network Structure and Function

Frontiers in Neuroscience, 2016

Probabilistic atlases of default mode, executive control and salience network white matter tracts: an fMRI-guided diffusion tensor imaging and tractography study

Frontiers in Human Neuroscience, 2015

The Review Editor Pew-Thian Yap declares that, despite being affiliated with the same institution... more The Review Editor Pew-Thian Yap declares that, despite being affiliated with the same institution as the Associate Editor Charlotte A. Boettiger, the review process was handled objectively. The Review Editor Kenichi Oishi declares that, despite being affiliated with the same institution as the Author Susan Courtney, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.