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Ofer Pasternak

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YNIMG Journal 2022 Journal Article

Cross-site harmonization of multi-shell diffusion MRI measures based on rotational invariant spherical harmonics (RISH)

  • Alberto de Luca
  • Suheyla Cetin Karayumak
  • Alexander Leemans
  • Yogesh Rathi
  • Stephan Swinnen
  • Jolien Gooijers
  • Amanda Clauwaert
  • Roald Bahr

Quantification methods based on the acquisition of diffusion magnetic resonance imaging (dMRI) with multiple diffusion weightings (e.g., multi-shell) are becoming increasingly applied to study the in-vivo brain. Compared to single-shell data for diffusion tensor imaging (DTI), multi-shell data allows to apply more complex models such as diffusion kurtosis imaging (DKI), which attempts to capture both diffusion hindrance and restriction effects, or biophysical models such as NODDI, which attempt to increase specificity by separating biophysical components. Because of the strong dependence of the dMRI signal on the measurement hardware, DKI and NODDI metrics show scanner and site differences, much like other dMRI metrics. These effects limit the implementation of multi-shell approaches in multicenter studies, which are needed to collect large sample sizes for robust analyses. Recently, a post-processing technique based on rotation invariant spherical harmonics (RISH) features was introduced to mitigate cross-scanner differences in DTI metrics. Unlike statistical harmonization methods, which require repeated application to every dMRI metric of choice, RISH harmonization is applied once on the raw data, and can be followed by any analysis. RISH features harmonization has been tested on DTI features but not its generalizability to harmonize multi-shell dMRI. In this work, we investigated whether performing the RISH features harmonization of multi-shell dMRI data removes cross-site differences in DKI and NODDI metrics while retaining longitudinal effects. To this end, 46 subjects underwent a longitudinal (up to 3 time points) two-shell dMRI protocol at 3 imaging sites. DKI and NODDI metrics were derived before and after harmonization and compared both at the whole brain level and at the voxel level. Then, the harmonization effects on cross-sectional and on longitudinal group differences were evaluated. RISH features averaged for each of the 3 sites exhibited prominent between-site differences in the frontal and posterior part of the brain. Statistically significant differences in fractional anisotropy, mean diffusivity and mean kurtosis were observed both at the whole brain and voxel level between all the acquisition sites before harmonization, but not after. The RISH method also proved effective to harmonize NODDI metrics, particularly in white matter. The RISH based harmonization maintained the magnitude and variance of longitudinal changes as compared to the non-harmonized data of all considered metrics. In conclusion, the application of RISH feature based harmonization to multi-shell dMRI data can be used to remove cross-site differences in DKI metrics and NODDI analyses, while retaining inherent relations between longitudinal acquisitions.

YNIMG Journal 2022 Journal Article

Free water diffusion MRI and executive function with a speed component in healthy aging

  • Martin Berger
  • Lukas Pirpamer
  • Edith Hofer
  • Stefan Ropele
  • Marco Duering
  • Benno Gesierich
  • Ofer Pasternak
  • Christian Enzinger

Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons. We examined 226 healthy elderly participants (median age 69. 83 years, IQR: 56. 99–74. 42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression. Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0. 213 – 0. 266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R2=0. 421, p = 0. 018) and the corpus callosum (genu (R 2 = 0. 418, p = 0. 021), prefrontal (R 2 = 0. 416, p = 0. 026), premotor (R 2 = 0. 418, p = 0. 021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance. In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.

YNIMG Journal 2021 Journal Article

Deep learning based segmentation of brain tissue from diffusion MRI

  • Fan Zhang
  • Anna Breger
  • Kang Ik Kevin Cho
  • Lipeng Ning
  • Carl-Fredrik Westin
  • Lauren J. O’Donnell
  • Ofer Pasternak

Segmentation of brain tissue types from diffusion MRI (dMRI) is an important task, required for quantification of brain microstructure and for improving tractography. Current dMRI segmentation is mostly based on anatomical MRI (e.g., T1- and T2-weighted) segmentation that is registered to the dMRI space. However, such inter-modality registration is challenging due to more image distortions and lower image resolution in dMRI as compared with anatomical MRI. In this study, we present a deep learning method for diffusion MRI segmentation, which we refer to as DDSeg. Our proposed method learns tissue segmentation from high-quality imaging data from the Human Connectome Project (HCP), where registration of anatomical MRI to dMRI is more precise. The method is then able to predict a tissue segmentation directly from new dMRI data, including data collected with different acquisition protocols, without requiring anatomical data and inter-modality registration. We train a convolutional neural network (CNN) to learn a tissue segmentation model using a novel augmented target loss function designed to improve accuracy in regions of tissue boundary. To further improve accuracy, our method adds diffusion kurtosis imaging (DKI) parameters that characterize non-Gaussian water molecule diffusion to the conventional diffusion tensor imaging parameters. The DKI parameters are calculated from the recently proposed mean-kurtosis-curve method that corrects implausible DKI parameter values and provides additional features that discriminate between tissue types. We demonstrate high tissue segmentation accuracy on HCP data, and also when applying the HCP-trained model on dMRI data from other acquisitions with lower resolution and fewer gradient directions.

YNIMG Journal 2021 Journal Article

MK-Curve improves sensitivity to identify white matter alterations in clinical high risk for psychosis

  • Fan Zhang
  • Kang Ik Kevin Cho
  • Yingying Tang
  • Tianhong Zhang
  • Sinead Kelly
  • Maria Di Biase
  • Lihua Xu
  • Huijun Li

Diffusion kurtosis imaging (DKI) is a diffusion MRI approach that enables the measurement of brain microstructural properties, reflecting molecular restrictions and tissue heterogeneity. DKI parameters such as mean kurtosis (MK) provide additional subtle information to that provided by popular diffusion tensor imaging (DTI) parameters, and thus have been considered useful to detect white matter abnormalities, especially in populations that are not expected to show severe brain pathologies. However, DKI parameters often yield artifactual output values that are outside of the biologically plausible range, which diminish sensitivity to identify true microstructural changes. Recently we have proposed the mean-kurtosis-curve (MK-Curve) method to correct voxels with implausible DKI parameters, and demonstrated its improved performance against other approaches that correct artifacts in DKI. In this work, we aimed to evaluate the utility of the MK-Curve method to improve the identification of white matter abnormalities in group comparisons. To do so, we compared group differences, with and without the MK-Curve correction, between 115 individuals at clinical high risk for psychosis (CHR) and 93 healthy controls (HCs). We also compared the correlation of the corrected and uncorrected DKI parameters with clinical characteristics. Following the MK-curve correction, the group differences had larger effect sizes and higher statistical significance (i.e., lower p-values), demonstrating increased sensitivity to detect group differences, in particular in MK. Furthermore, the MK-curve-corrected DKI parameters displayed stronger correlations with clinical variables in CHR individuals, demonstrating the clinical relevance of the corrected parameters. Overall, following the MK-curve correction our analyses found widespread lower MK in CHR that overlapped with lower fractional anisotropy (FA), and both measures were significantly correlated with a decline in functioning and with more severe symptoms. These observations further characterize white matter alterations in the CHR stage, demonstrating that MK and FA abnormalities are widespread, and mostly overlap. The improvement in group differences and stronger correlation with clinical variables suggest that applying MK-curve would be beneficial for the detection and characterization of subtle group differences in other experiments as well.

YNICL Journal 2020 Journal Article

Brain functional connectivity data enhance prediction of clinical outcome in youth at risk for psychosis

  • Guusje Collin
  • Alfonso Nieto-Castanon
  • Martha E. Shenton
  • Ofer Pasternak
  • Sinead Kelly
  • Matcheri S. Keshavan
  • Larry J. Seidman
  • Robert W. McCarley

The first episode of psychosis is typically preceded by a prodromal phase with subthreshold symptoms and functional decline. Improved outcome prediction in this stage is needed to allow targeted early intervention. This study assesses a combined clinical and resting-state fMRI prediction model in 137 adolescents and young adults at Clinical High Risk (CHR) for psychosis from the Shanghai At Risk for Psychosis (SHARP) program. Based on outcome at one-year follow-up, participants were separated into three outcome categories including good outcome (symptom remission, N = 71), intermediate outcome (ongoing CHR symptoms, N = 30), and poor outcome (conversion to psychosis or treatment-refractory, N = 36). Validated clinical predictors from the psychosis-risk calculator were combined with measures of resting-state functional connectivity. Using multinomial logistic regression analysis and leave-one-out cross-validation, a clinical-only prediction model did not achieve a significant level of outcome prediction (F1 = 0. 32, p =. 154). An imaging-only model yielded a significant prediction model (F 1 = 0. 41, p =. 016), but a combined model including both clinical and connectivity measures showed the best performance (F1 = 0. 46, p <. 001). Influential predictors in this model included functional decline, verbal learning performance, a family history of psychosis, default-mode and frontoparietal within-network connectivity, and between-network connectivity among language, salience, dorsal attention, sensorimotor, and cerebellar networks. These findings suggest that brain changes reflected by alterations in functional connectivity may be useful for outcome prediction in the prodromal stage.

YNICL Journal 2020 Journal Article

Mild traumatic brain injury impacts associations between limbic system microstructure and post-traumatic stress disorder symptomatology

  • Valerie J. Sydnor
  • Sylvain Bouix
  • Ofer Pasternak
  • Elisabeth Hartl
  • Laura Levin-Gleba
  • Benjamin Reid
  • Yorghos Tripodis
  • Jeffrey P. Guenette

BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. METHODS: Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. RESULTS: Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. CONCLUSIONS: These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

YNIMG Journal 2020 Journal Article

The association of white matter free water with cognition in older adults

  • Joseph M. Gullett
  • Andrew O’Shea
  • Damon G. Lamb
  • Eric C. Porges
  • Deirdre M. O’Shea
  • Ofer Pasternak
  • Ronald A. Cohen
  • Adam J. Woods

Background Extracellular free water within cerebral white matter tissue has been shown to increase with age and pathology, yet the cognitive consequences of free water in typical aging prior to the development of neurodegenerative disease remains unclear. Understanding the contribution of free water to cognitive function in older adults may provide important insight into the neural mechanisms of the cognitive aging process. Methods A diffusion-weighted MRI measure of extracellular free water as well as a commonly used diffusion MRI metric (fractional anisotropy) along nine bilateral white matter pathways were examined for their relationship with cognitive function assessed by the NIH Toolbox Cognitive Battery in 47 older adults (mean age ​= ​74. 4 years, SD ​= ​5. 4 years, range ​= ​65–85 years). Probabilistic tractography at the 99th percentile level of probability (Tracts Constrained by Underlying Anatomy; TRACULA) was utilized to produce the pathways on which microstructural characteristics were overlaid and examined for their contribution to cognitive function independent of age, education, and gender. Results When examining the 99th percentile probability core white matter pathway derived from TRACULA, poorer fluid cognitive ability was related to higher mean free water values across the angular and cingulum bundles of the cingulate gyrus, as well as the corticospinal tract and the superior longitudinal fasciculus. There was no relationship between cognition and mean FA or free water-adjusted FA across the 99th percentile core white matter pathway. Crystallized cognitive ability was not associated with any of the diffusion measures. When examining cognitive domains comprising the NIH Toolbox Fluid Cognition index relationships with these white matter pathways, mean free water demonstrated strong hemispheric and functional specificity for cognitive performance, whereas mean FA was not related to age or cognition across the 99th percentile pathway. Conclusions Extracellular free water within white matter appears to increase with normal aging, and higher values are associated with significantly lower fluid but not crystallized cognitive functions. When using TRACULA to estimate the core of a white matter pathway, a higher degree of free water appears to be highly specific to the pathways associated with memory, working memory, and speeded decision-making performance, whereas no such relationship existed with FA. These data suggest that free water may play an important role in the cognitive aging process, and may serve as a stronger and more specific indicator of early cognitive decline than traditional diffusion MRI measures, such as FA.

YNICL Journal 2019 Journal Article

Abnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome

  • Zora Kikinis
  • Nikos Makris
  • Valerie J. Sydnor
  • Sylvain Bouix
  • Ofer Pasternak
  • Ioana L. Coman
  • Kevin M. Antshel
  • Wanda Fremont

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits.

YNIMG Journal 2019 Journal Article

MK-curve - Characterizing the relation between mean kurtosis and alterations in the diffusion MRI signal

  • Fan Zhang
  • Lipeng Ning
  • Lauren J. O'Donnell
  • Ofer Pasternak

Diffusion kurtosis imaging (DKI) is a diffusion MRI (dMRI) technique to quantify brain microstructural properties. While DKI measures are sensitive to tissue alterations, they are also affected by signal alterations caused by imaging artifacts such as noise, motion and Gibbs ringing. Consequently, DKI often yields output parameter values (e. g. mean kurtosis; MK) that are implausible. These include implausible values that are outside of the range dictated by physics/biology, and visually apparent implausible values that form unexpected discontinuities, being too high or too low comparing with their neighborhood. These implausible values will introduce bias into any following data analyses (e. g. between-population statistical computation). Existing studies have attempted to correct implausible DKI parameter values in multiple ways; however, these approaches are not always effective. In this study, we propose a novel method for detecting and correcting voxels with implausible values to enable improved DKI parameter estimation. In particular, we focus on MK parameter estimation. We first characterize the relation between MK and alterations in the dMRI signal including diffusion weighted images (DWIs) and the baseline (b0) images. This is done by calculating MK for a range of synthetic DWI or b0 for each voxel, and generating curves (MK-curve) representing how alterations to the input dMRI signals affect the resulting output MK. We find that voxels with implausible MK values are more likely caused by artifacts in the b0 images than artifacts in DWIs with higher b-values. Accordingly, two characteristic b0 values, which define a range of synthetic b0 values that generate implausible MK values, are identified on the MK-curve. Based on this characterization, we propose an automatic approach for detection of voxels with implausible MK values by comparing a voxel's original b0 signal to the identified two characteristic b0 values, along with a correction strategy to replace the original b0 in each detected implausible voxel with a synthetic b0 value computed from the MK-curve. We evaluate the method on a DKI phantom dataset and dMRI datasets from the Human Connectome Project (HCP), and we compare the proposed correction method with other previously proposed correction methods. Results show that our proposed method is able to identify and correct most voxels with implausible DKI parameter values as well as voxels with implausible diffusion tensor parameter values.

YNIMG Journal 2018 Journal Article

Advances in microstructural diffusion neuroimaging for psychiatric disorders

  • Ofer Pasternak
  • Sinead Kelly
  • Valerie J. Sydnor
  • Martha E. Shenton

Understanding the neuropathological underpinnings of mental disorders such as schizophrenia, major depression, and bipolar disorder is an essential step towards the development of targeted treatments. Diffusion MRI studies utilizing the diffusion tensor imaging (DTI) model have been extremely successful to date in identifying microstructural brain abnormalities in individuals suffering from mental illness, especially in regions of white matter, although identified abnormalities have been biologically non-specific. Building on DTI's success, in recent years more advanced diffusion MRI methods have been developed and applied to the study of psychiatric populations, with the aim of offering increased sensitivity to subtle neurological abnormalities, as well as improved specificity to candidate pathologies such as demyelination and neuroinflammation. These advanced methods, however, usually come at the cost of prolonged imaging sequences or reduced signal to noise, and they are more difficult to evaluate compared with the more simplified approach taken by the now common DTI model. To date, a limited number of advanced diffusion MRI methods have been employed to study schizophrenia, major depression and bipolar disorder populations. In this review we survey these studies, compare findings across diverse methods, discuss the main benefits and limitations of the different methods, and assess the extent to which the application of more advanced diffusion imaging approaches has led to novel and transformative information with regards to our ability to better understand the etiology and pathology of mental disorders.

YNICL Journal 2018 Journal Article

Automated versus manual segmentation of brain region volumes in former football players

  • Jeffrey P. Guenette
  • Robert A. Stern
  • Yorghos Tripodis
  • Alicia S. Chua
  • Vivian Schultz
  • Valerie J. Sydnor
  • Nathaniel Somes
  • Sarina Karmacharya

Objectives: To determine whether or not automated FreeSurfer segmentation of brain regions considered important in repetitive head trauma can be analyzed accurately without manual correction. Materials and methods: 3 T MR neuroimaging was performed with automated FreeSurfer segmentation and manual correction of 11 brain regions in former National Football League (NFL) players with neurobehavioral symptoms and in control subjects. Automated segmentation and manually-corrected volumes were compared using an intraclass correlation coefficient (ICC). Linear mixed effects regression models were also used to estimate between-group mean volume comparisons and to correlate former NFL player brain volumes with neurobehavioral factors. Results: Eighty-six former NFL players (55.2 ± 8.0 years) and 22 control subjects (57.0 ± 6.6 years) were evaluated. ICC was highly correlated between automated and manually-corrected corpus callosum volumes (0.911), lateral ventricular volumes (right 0.980, left 0.967), and amygdala-hippocampal complex volumes (right 0.713, left 0.731), but less correlated when amygdalae (right -0.170, left -0.090) and hippocampi (right 0.539, left 0.637) volumes were separately delineated and also less correlated for cingulate gyri volumes (right 0.639, left 0.351). Statistically significant differences between former NFL player and controls were identified in 8 of 11 regions with manual correction but in only 4 of 11 regions without such correction. Within NFL players, manually corrected brain volumes were significantly associated with 3 neurobehavioral factors, but a different set of 3 brain regions and neurobehavioral factor correlations was observed for brain region volumes segmented without manual correction. Conclusions: Automated FreeSurfer segmentation of the corpus callosum, lateral ventricles, and amygdala-hippocampus complex may be appropriate for analysis without manual correction. However, FreeSurfer segmentation of the amygdala, hippocampus, and cingulate gyrus need further manual correction prior to performing group comparisons and correlations with neurobehavioral measures.

YNICL Journal 2018 Journal Article

Sex differences in white matter alterations following repetitive subconcussive head impacts in collegiate ice hockey players

  • Nico Sollmann
  • Paul S. Echlin
  • Vivian Schultz
  • Petra V. Viher
  • Amanda E. Lyall
  • Yorghos Tripodis
  • David Kaufmann
  • Elisabeth Hartl

OBJECTIVE: Repetitive subconcussive head impacts (RSHI) may lead to structural, functional, and metabolic alterations of the brain. While differences between males and females have already been suggested following a concussion, whether there are sex differences following exposure to RSHI remains unknown. The aim of this study was to identify and to characterize sex differences following exposure to RSHI. METHODS: Twenty-five collegiate ice hockey players (14 males and 11 females, 20.6 ± 2.0 years), all part of the Hockey Concussion Education Project (HCEP), underwent diffusion-weighted magnetic resonance imaging (dMRI) before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011-2012 and did not experience a concussion during the season. Whole-brain tract-based spatial statistics (TBSS) were used to compare pre- and postseason imaging in both sexes for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Pre- and postseason neurocognitive performance were assessed by the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). RESULTS: Significant differences between the sexes were primarily located within the superior longitudinal fasciculus (SLF), the internal capsule (IC), and the corona radiata (CR) of the right hemisphere (RH). In significant voxel clusters (p < 0.05), decreases in FA (absolute difference pre- vs. postseason: 0.0268) and increases in MD (0.0002), AD (0.00008), and RD (0.00005) were observed in females whereas males showed no significant changes. There was no significant correlation between the change in diffusion scalar measures over the course of the season and neurocognitive performance as evidenced from postseason ImPACT scores. CONCLUSIONS: The results of this study suggest sex differences in structural alterations following exposure to RSHI. Future studies need to investigate further the underlying mechanisms and association with exposure and clinical outcomes.

YNICL Journal 2017 Journal Article

Performance of unscented Kalman filter tractography in edema: Analysis of the two-tensor model

  • Ruizhi Liao
  • Lipeng Ning
  • Zhenrui Chen
  • Laura Rigolo
  • Shun Gong
  • Ofer Pasternak
  • Alexandra J. Golby
  • Yogesh Rathi

Diffusion MRI tractography is increasingly used in pre-operative neurosurgical planning to visualize critical fiber tracts. However, a major challenge for conventional tractography, especially in patients with brain tumors, is tracing fiber tracts that are affected by vasogenic edema, which increases water content in the tissue and lowers diffusion anisotropy. One strategy for improving fiber tracking is to use a tractography method that is more sensitive than the traditional single-tensor streamline tractography. We performed experiments to assess the performance of two-tensor unscented Kalman filter (UKF) tractography in edema. UKF tractography fits a diffusion model to the data during fiber tracking, taking advantage of prior information from the previous step along the fiber. We studied UKF performance in a synthetic diffusion MRI digital phantom with simulated edema and in retrospective data from two neurosurgical patients with edema affecting the arcuate fasciculus and corticospinal tracts. We compared the performance of several tractography methods including traditional streamline, UKF single-tensor, and UKF two-tensor. To provide practical guidance on how the UKF method could be employed, we evaluated the impact of using various seed regions both inside and outside the edematous regions, as well as the impact of parameter settings on the tractography sensitivity. We quantified the sensitivity of different methods by measuring the percentage of the patient-specific fMRI activation that was reached by the tractography. We expected that diffusion anisotropy threshold parameters, as well as the inclusion of a free water model, would significantly influence the reconstruction of edematous WM fiber tracts, because edema increases water content in the tissue and lowers anisotropy. Contrary to our initial expectations, varying the fractional anisotropy threshold and including a free water model did not affect the UKF two-tensor tractography output appreciably in these two patient datasets. The most effective parameter for increasing tracking sensitivity was the generalized anisotropy (GA) threshold, which increased the length of tracked fibers when reduced to 0.075. In addition, the most effective seeding strategy was seeding in the whole brain or in a large region outside of the edema. Overall, the main contribution of this study is to provide insight into how UKF tractography can work, using a two-tensor model, to begin to address the challenge of fiber tract reconstruction in edematous regions near brain tumors.

YNIMG Journal 2017 Journal Article

Separating blood and water: Perfusion and free water elimination from diffusion MRI in the human brain

  • Anna S. Rydhög
  • Filip Szczepankiewicz
  • Ronnie Wirestam
  • André Ahlgren
  • Carl-Fredrik Westin
  • Linda Knutsson
  • Ofer Pasternak

The assessment of the free water fraction in the brain provides important information about extracellular processes such as atrophy and neuroinflammation in various clinical conditions as well as in normal development and aging. Free water estimates from diffusion MRI are assumed to account for freely diffusing water molecules in the extracellular space, but may be biased by other pools of molecules in rapid random motion, such as the intravoxel incoherent motion (IVIM) of blood, where water molecules perfuse in the randomly oriented capillary network. The goal of this work was to separate the signal contribution of the perfusing blood from that of free-water and of other brain diffusivities. The influence of the vascular compartment on the estimation of the free water fraction and other diffusivities was investigated by simulating perfusion in diffusion MRI data. The perfusion effect in the simulations was significant, especially for the estimation of the free water fraction, and was maintained as long as low b-value data were included in the analysis. Two approaches to reduce the perfusion effect were explored in this study: (i) increasing the minimal b-value used in the fitting, and (ii) using a three-compartment model that explicitly accounts for water molecules in the capillary blood. Estimation of the model parameters while excluding low b-values reduced the perfusion effect but was highly sensitive to noise. The three-compartment model fit was more stable and additionally, provided an estimation of the volume fraction of the capillary blood compartment. The three-compartment model thus disentangles the effects of free water diffusion and perfusion, which is of major clinical importance since changes in these components in the brain may indicate different pathologies, i. e. , those originating from the extracellular space, such as neuroinflammation and atrophy, and those related to the vascular space, such as vasodilation, vasoconstriction and capillary density. Diffusion MRI data acquired from a healthy volunteer, using multiple b-shells, demonstrated an expected non-zero contribution from the blood fraction, and indicated that not accounting for the perfusion effect may explain the overestimation of the free water fraction evinced in previous studies. Finally, the applicability of the method was demonstrated with a dataset acquired using a clinically feasible protocol with shorter acquisition time and fewer b-shells.

YNICL Journal 2016 Journal Article

Abnormal white matter microstructure and increased extracellular free-water in the cingulum bundle associated with delusions in chronic schizophrenia

  • Lena K.L. Oestreich
  • Ofer Pasternak
  • Martha E. Shenton
  • Marek Kubicki
  • Xue Gong
  • Simon McCarthy-Jones
  • Thomas J. Whitford

BACKGROUND: There is growing evidence to suggest that delusions associated with schizophrenia arise from altered structural brain connectivity. The present study investigated whether structural changes in three major fasciculi that interconnect the limbic system - the cingulum bundle, uncinate fasciculus and fornix - are associated with delusions in chronic schizophrenia patients. METHODS: Free-water corrected Diffusion Tensor Imaging was used to investigate the association between delusions and both microstructural changes within these three fasciculi and extracellular changes in the surrounding free-water. Clinical data and diffusion MRI scans were obtained from 28 healthy controls and 86 schizophrenia patients, of whom 34 had present state delusions, 35 had a lifetime history but currently remitted delusions, and 17 had never experienced delusions. RESULTS: While present state and remitted delusions were found to be associated with reduced free-water corrected fractional anisotropy (FAT) and increased free-water corrected radial diffusivity (RDT) in the cingulum bundle bilaterally, extracellular free-water (FW) in the left cingulum bundle was found to be specifically associated with present state delusions in chronic schizophrenia. No changes were observed in the remaining tracts. CONCLUSIONS: These findings suggest that state and trait delusions in chronic schizophrenia are associated with microstructural processes, such as myelin abnormalities (as indicated by decreased FAT and increased RDT) in the cingulum bundle and that state delusions are additionally associated with extracellular processes such as neuroinflammation or atrophy (as indicated by increased FW) in the left cingulum bundle.

YNICL Journal 2016 Journal Article

Applying a free-water correction to diffusion imaging data uncovers stress-related neural pathology in depression

  • Maurizio Bergamino
  • Ofer Pasternak
  • Madison Farmer
  • Martha E. Shenton
  • J. Paul Hamilton

Diffusion tensor imaging (DTI) holds promise for developing our understanding of white-matter pathology in major depressive disorder (MDD). Variable findings in DTI-based investigations of MDD, however, have thwarted development of this literature. Effects of extra-cellular free-water on the sensitivity of DTI metrics could account for some of this inconsistency. Here we investigated whether applying a free-water correction algorithm to DTI data could improve the sensitivity to detect clinical effects using DTI metrics. Only after applying this correction, we found: a) significantly decreased fractional anisotropy and axial diffusivity (AD) in the left inferior fronto-occipital fasciculus (IFOF) in MDD; and b) increased self-reported stress that significantly correlated with decreased IFOF AD in depression. We estimated and confirmed the robustness of differences observed between free-water corrected and uncorrected approaches using bootstrapping. We conclude that applying a free-water correction to DTI data increases the sensitivity of DTI-based metrics to detect clinical effects in MDD.

YNIMG Journal 2016 Journal Article

Q-space trajectory imaging for multidimensional diffusion MRI of the human brain

  • Carl-Fredrik Westin
  • Hans Knutsson
  • Ofer Pasternak
  • Filip Szczepankiewicz
  • Evren Özarslan
  • Danielle van Westen
  • Cecilia Mattisson
  • Mats Bogren

This work describes a new diffusion MR framework for imaging and modeling of microstructure that we call q-space trajectory imaging (QTI). The QTI framework consists of two parts: encoding and modeling. First we propose q-space trajectory encoding, which uses time-varying gradients to probe a trajectory in q-space, in contrast to traditional pulsed field gradient sequences that attempt to probe a point in q-space. Then we propose a microstructure model, the diffusion tensor distribution (DTD) model, which takes advantage of additional information provided by QTI to estimate a distributional model over diffusion tensors. We show that the QTI framework enables microstructure modeling that is not possible with the traditional pulsed gradient encoding as introduced by Stejskal and Tanner. In our analysis of QTI, we find that the well-known scalar b-value naturally extends to a tensor-valued entity, i. e. , a diffusion measurement tensor, which we call the b-tensor. We show that b-tensors of rank 2 or 3 enable estimation of the mean and covariance of the DTD model in terms of a second order tensor (the diffusion tensor) and a fourth order tensor. The QTI framework has been designed to improve discrimination of the sizes, shapes, and orientations of diffusion microenvironments within tissue. We derive rotationally invariant scalar quantities describing intuitive microstructural features including size, shape, and orientation coherence measures. To demonstrate the feasibility of QTI on a clinical scanner, we performed a small pilot study comparing a group of five healthy controls with five patients with schizophrenia. The parameter maps derived from QTI were compared between the groups, and 9 out of the 14 parameters investigated showed differences between groups. The ability to measure and model the distribution of diffusion tensors, rather than a quantity that has already been averaged within a voxel, has the potential to provide a powerful paradigm for the study of complex tissue architecture.

YNICL Journal 2015 Journal Article

Reconstruction of the arcuate fasciculus for surgical planning in the setting of peritumoral edema using two-tensor unscented Kalman filter tractography

  • Zhenrui Chen
  • Yanmei Tie
  • Olutayo Olubiyi
  • Laura Rigolo
  • Alireza Mehrtash
  • Isaiah Norton
  • Ofer Pasternak
  • Yogesh Rathi

BACKGROUND: Diffusion imaging tractography is increasingly used to trace critical fiber tracts in brain tumor patients to reduce the risk of post-operative neurological deficit. However, the effects of peritumoral edema pose a challenge to conventional tractography using the standard diffusion tensor model. The aim of this study was to present a novel technique using a two-tensor unscented Kalman filter (UKF) algorithm to track the arcuate fasciculus (AF) in brain tumor patients with peritumoral edema. METHODS: Ten right-handed patients with left-sided brain tumors in the vicinity of language-related cortex and evidence of significant peritumoral edema were retrospectively selected for the study. All patients underwent 3-Tesla magnetic resonance imaging (MRI) including a diffusion-weighted dataset with 31 directions. Fiber tractography was performed using both single-tensor streamline and two-tensor UKF tractography. A two-regions-of-interest approach was applied to perform the delineation of the AF. Results from the two different tractography algorithms were compared visually and quantitatively. RESULTS: Using single-tensor streamline tractography, the AF appeared disrupted in four patients and contained few fibers in the remaining six patients. Two-tensor UKF tractography delineated an AF that traversed edematous brain areas in all patients. The volume of the AF was significantly larger on two-tensor UKF than on single-tensor streamline tractography (p < 0.01). CONCLUSIONS: Two-tensor UKF tractography provides the ability to trace a larger volume AF than single-tensor streamline tractography in the setting of peritumoral edema in brain tumor patients.

YNIMG Journal 2012 Journal Article

How and how not to correct for CSF-contamination in diffusion MRI

  • Claudia Metzler-Baddeley
  • Michael J. O'Sullivan
  • Sonya Bells
  • Ofer Pasternak
  • Derek K. Jones

Diffusion MRI is used extensively to investigate changes in white matter microstructure related to brain development and pathology. Ageing, however, is also associated with significant white and grey matter loss which in turn can lead to cerebrospinal fluid (CSF) based partial volume artefacts in diffusion MRI metrics. This is especially problematic in regions prone to CSF contamination, such as the fornix and the genu of corpus callosum, structures that pass through or close to the ventricles respectively. The aim of this study was to model the effects of CSF contamination on diffusion MRI metrics, and to evaluate different post-acquisition strategies to correct for CSF-contamination: Controlling for whole brain volume and correcting on a voxel-wise basis using the Free Water Elimination (FWE) approach. Using the fornix as an exemplar of a structure prone to CSF-contamination, corrections were applied to tract-specific and voxel-based [tract based spatial statistics (TBSS)] analyses of empirical DT-MRI data from 39 older adults (53–93years of age). In addition to significant age-related decreases in whole brain volume and fornix tissue volume fraction, age was also associated with a reduction in mean fractional anisotropy and increase in diffusivity metrics in the fornix. The experimental data agreed with the simulations in that diffusivity metrics (mean diffusivity, axial and radial diffusivity) were more prone to partial volume CSF-contamination errors than fractional anisotropy. After FWE-based voxel-by-voxel partial volume corrections, the significant positive correlations between age and diffusivity metrics, in particular with axial diffusivity, disappeared whereas the correlation with anisotropy remained. In contrast, correcting for whole brain volume had little effect in removing these spurious correlations. Our study highlights the importance of correcting for CSF-contamination partial volume effects in the structures of interest on a voxel-by-voxel basis prior to drawing inferences about underlying changes in white matter structures and have implications for the interpretation of many recent diffusion MRI results in ageing and disease.

YNIMG Journal 2010 Journal Article

Structural correlates of memory performance with diffusion tensor imaging

  • Efrat Sasson
  • Glen M. Doniger
  • Ofer Pasternak
  • Yaniv Assaf

Aging is associated with a variety of structural and pathological brain changes. Memory, or the ability to store and retrieve information, declines significantly during aging. In order to characterize the brain micro-structural correlates of memory performance, 52 healthy subjects, age 25–82 years, completed a computerized non-verbal memory test and were scanned using magnetic resonance diffusion tensor imaging. Partial correlation was conducted between DTI parameters and memory performance (accuracy and reaction time (RT) for different learning stages) controlling for age. A similar correlation pattern was found for apparent diffusion coefficient (ADC), FA, and radial and axial diffusivities, but correlations between ADC and memory performance were the most informative and are therefore reported here. While ADC was correlated with accuracy mainly in temporal and frontal cortical regions, it was correlated with RT in temporal and frontal white matter pathways, including the inferior longitudinal fasciculus and uncinate fasciculus. The task was repeated four times, performance in the first repetition was correlated with ADC in frontal white matter and in the fourth repetition with ADC in temporal gray matter structures mainly the parahippocapus and in the middle temporal gyrus. The localization of the correlations of ADC with the different task parameters is in line with previous studies. Thus, inter-subject variability in memory performance and tissue morphology, as expressed by diffusion tensor magnetic resonance imaging, can be used to relate tissue microstructures with cognitive performance, and to provide information to corroborate other functional localization techniques.

YNIMG Journal 2010 Journal Article

The effect of metric selection on the analysis of diffusion tensor MRI data

  • Ofer Pasternak
  • Nir Sochen
  • Peter J. Basser

The measurement of the distance between diffusion tensors is the foundation on which any subsequent analysis or processing of these quantities, such as registration, regularization, interpolation, or statistical inference is based. In recent years a family of Riemannian tensor metrics based on geometric considerations has been introduced for this purpose. In this work we examine the properties one would use to select metrics for diffusion tensors, diffusion coefficients, and diffusion weighted MR image data. We show that empirical evidence supports the use of a Euclidean metric for diffusion tensors, based upon Monte Carlo simulations. Our findings suggest that affine invariance is not a desirable property for a diffusion tensor metric because it leads to substantial biases in tensor data. Rather, the relationship between distribution and distance is suggested as a novel criterion for metric selection.

YNIMG Journal 2009 Journal Article

Cluster analysis of resting-state fMRI time series

  • Aviv Mezer
  • Yossi Yovel
  • Ofer Pasternak
  • Tali Gorfine
  • Yaniv Assaf

Functional MRI (fMRI) has become one of the leading methods for brain mapping in neuroscience. Recent advances in fMRI analysis were used to define the default state of brain activity, functional connectivity and basal activity. Basal activity measured with fMRI raised tremendous interest among neuroscientists since synchronized brain activity pattern could be retrieved while the subject rests (resting state fMRI). During recent years, a few signal processing schemes have been suggested to analyze the resting state blood oxygenation level dependent (BOLD) signal from simple correlations to spectral decomposition. In most of these analysis schemes, the question asked was which brain areas “behave” in the time domain similarly to a pre-specified ROI. In this work we applied short time frequency analysis and clustering to study the spatial signal characteristics of resting state fMRI time series. Such analysis revealed that clusters of similar BOLD fluctuations are found in the cortex but also in the white matter and sub-cortical gray matter regions (thalamus). We found high similarities between the BOLD clusters and the neuro-anatomical appearance of brain regions. Additional analysis of the BOLD time series revealed a strong correlation between head movements and clustering quality. Experiments performed with T1-weighted time series also provided similar quality of clustering. These observations led us to the conclusion that non-functional contributions to the BOLD time series can also account for symmetric appearance of signal fluctuations. These contributions may include head motions, the underling microvasculature anatomy and cellular morphology.

YNIMG Journal 2006 Journal Article

Characterization of displaced white matter by brain tumors using combined DTI and fMRI

  • Tom Schonberg
  • Pazit Pianka
  • Talma Hendler
  • Ofer Pasternak
  • Yaniv Assaf

In vivo white matter tractography by diffusion tensor imaging (DTI) has become a popular tool for investigation of white matter architecture in the normal brain. Despite some unresolved issues regarding the accuracy of DTI, recent studies applied DTI for delineating white matter organization in the vicinity of brain lesions and especially brain tumors. Apart from the intrinsic limitations of DTI, the tracking of fibers in the vicinity or within lesions is further complicated due to changes in diseased tissue such as elevated water content (edema), tissue compression and degeneration. These changes deform the architecture of the white matter and in some cases prevent definite selection of the seed region of interest (ROI) from which fiber tracking begins. We show here that for displaced fiber systems, the use of anatomical approach for seed ROI selection yields insufficient results. Alternatively, we propose to select the seed points based on functional MRI activations which constrain the subjective seed ROI selection. The results are demonstrated on two major fiber systems: the pyramidal tract and the superior longitudinal fasciculus that connect critical motor and language areas, respectively. The fMRI based seed ROI selection approach enabled a more comprehensive mapping of these fiber systems. Furthermore, this procedure enabled the characterization of displaced white matter using the eigenvalue decomposition of DTI. We show that along the compressed fiber system, the diffusivity parallel to the fiber increases, while that perpendicular to the fibers decreases, leading to an overall increase in the fractional anisotropy index reflecting the compression of the fiber bundle. We conclude that definition of the functional network of a subject with deformed white matter should be done carefully. With fMRI, one can more accurately define the seed ROI for DTI based tractography and to provide a more comprehensive, functionally related, white matter mapping, a very important tool used in pre-surgical mapping.

NeurIPS Conference 2005 Conference Paper

Neuronal Fiber Delineation in Area of Edema from Diffusion Weighted MRI

  • Ofer Pasternak
  • Nathan Intrator
  • Nir Sochen
  • Yaniv Assaf

Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) is a non inva- sive method for brain neuronal fibers delineation. Here we show a mod- ification for DT-MRI that allows delineation of neuronal fibers which are infiltrated by edema. We use the Muliple Tensor Variational (MTV) framework which replaces the diffusion model of DT-MRI with a mul- tiple component model and fits it to the signal attenuation with a vari- ational regularization mechanism. In order to reduce free water con- tamination we estimate the free water compartment volume fraction in each voxel, remove it, and then calculate the anisotropy of the remaining compartment. The variational framework was applied on data collected with conventional clinical parameters, containing only six diffusion di- rections. By using the variational framework we were able to overcome the highly ill posed fitting. The results show that we were able to find fibers that were not found by DT-MRI.

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