Author name cluster

Markus Nilsson

Possible papers associated with this exact author name in Arrow. This page groups case-insensitive exact name matches and is not a full identity disambiguation profile.

20 papers

1 author row

YNIMG Journal 2024 Journal Article

Divergent functional connectivity changes associated with white matter hyperintensities

Alexander F. Santillo
Tor O. Strandberg
Nina H. Reislev
Markus Nilsson
Erik Stomrud
Nicola Spotorno
Danielle van Westen
Oskar Hansson

Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts. How change in functional connectivity is affected by white matter lesions and related to cognition (in the form of executive function and processing speed) was explored. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functional interregional lobar connectivity, which was related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increased intraregional functional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels' blood oxygenation level-dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by indicating novel mechanisms that may be important beyond this particular type of brain lesions.

YNIMG Journal 2023 Journal Article

Diffusion MRI with free gradient waveforms on a high-performance gradient system: Probing restriction and exchange in the human brain

Arthur Chakwizira
Ante Zhu
Thomas Foo
Carl-Fredrik Westin
Filip Szczepankiewicz
Markus Nilsson

The dependence of the diffusion MRI signal on the diffusion time carries signatures of restricted diffusion and exchange. Here we seek to highlight these signatures in the human brain by performing experiments using free gradient waveforms designed to be selectively sensitive to the two effects. We examine six healthy volunteers using both strong and ultra-strong gradients (80, 200 and 300 mT/m). In an experiment featuring a large set of 150 gradient waveforms with different sensitivities to restricted diffusion and exchange, our results reveal unique and different time-dependence signatures in grey and white matter. Grey matter was characterised by both restricted diffusion and exchange and white matter predominantly by restricted diffusion. Exchange in grey matter was at least twice as fast as in white matter, across all subjects and all gradient strengths. The cerebellar cortex featured relatively short exchange times (115 ms). Furthermore, we show that gradient waveforms with tailored designs can be used to map exchange in the human brain. We also assessed the feasibility of clinical applications of the method used in this work and found that the exchange-related contrast obtained with a 25-minute protocol at 300 mT/m was preserved in a 4-minute protocol at 300 mT/m and a 10-minute protocol at 80 mT/m. Our work underlines the utility of free waveforms for detecting time dependence signatures due to restricted diffusion and exchange in vivo, which may potentially serve as a tool for studying diseased tissue.

YNICL Journal 2023 Journal Article

Meningioma microstructure assessed by diffusion MRI: An investigation of the source of mean diffusivity and fractional anisotropy by quantitative histology

Jan Brabec
Magda Friedjungová
Daniel Vašata
Elisabet Englund
Johan Bengzon
Linda Knutsson
Filip Szczepankiewicz
Danielle van Westen

BACKGROUND: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level. PURPOSE: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters. MATERIALS AND METHODS: , respectively. RESULTS: is high in the presence of elongated and aligned cell structures, but low otherwise. CONCLUSION: across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD.

YNIMG Journal 2023 Journal Article

Probing brain tissue microstructure with MRI: principles, challenges, and the role of multidimensional diffusion-relaxation encoding

Björn Lampinen
Filip Szczepankiewicz
Jimmy Lätt
Linda Knutsson
Johan Mårtensson
Isabella M. Björkman-Burtscher
Danielle van Westen
Pia C. Sundgren

Diffusion MRI uses the random displacement of water molecules to sensitize the signal to brain microstructure and to properties such as the density and shape of cells. Microstructure modeling techniques aim to estimate these properties from acquired data by separating the signal between virtual tissue ‘compartments’ such as the intra-neurite and the extra-cellular space. A key challenge is that the diffusion MRI signal is relatively featureless compared with the complexity of brain tissue. Another challenge is that the tissue microstructure is wildly different within the gray and white matter of the brain. In this review, we use results from multidimensional diffusion encoding techniques to discuss these challenges and their tentative solutions. Multidimensional encoding increases the information content of the data by varying not only the b-value and the encoding direction but also additional experimental parameters such as the shape of the b-tensor and the echo time. Three main insights have emerged from such encoding. First, multidimensional data contradict common model assumptions on diffusion and T2 relaxation, and illustrates how the use of these assumptions cause erroneous interpretations in both healthy brain and pathology. Second, many model assumptions can be dispensed with if data are acquired with multidimensional encoding. The necessary data can be easily acquired in vivo using protocols optimized to minimize Cramér-Rao lower bounds. Third, microscopic diffusion anisotropy reflects the presence of axons but not dendrites. This insight stands in contrast to current ‘neurite models’ of brain tissue, which assume that axons in white matter and dendrites in gray matter feature highly similar diffusion. Nevertheless, as an axon-based contrast, microscopic anisotropy can differentiate gray and white matter when myelin alterations confound conventional MRI contrasts.

YNICL Journal 2023 Journal Article

Structural and microstructural thalamocortical network disruption in sporadic behavioural variant frontotemporal dementia

David Jakabek
Brian D. Power
Nicola Spotorno
Matthew D. Macfarlane
Mark Walterfang
Dennis Velakoulis
Christer Nilsson
Maria Landqvist Waldö

Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

YNICL Journal 2023 Journal Article

Ultra-strong diffusion-weighted MRI reveals cerebellar grey matter abnormalities in movement disorders

Chantal M.W. Tax
Sila Genc
Claire L MacIver
Markus Nilsson
Mark Wardle
Filip Szczepankiewicz
Derek K. Jones
Kathryn J. Peall

Structural brain MRI has proven invaluable in understanding movement disorder pathophysiology. However, most work has focused on grey/white matter volumetric (macrostructural) and white matter microstructural effects, limiting understanding of frequently implicated grey matter microstructural differences. Using ultra-strong spherical tensor encoding diffusion-weighted MRI, a persistent MRI signal was seen in healthy cerebellar grey matter even at high diffusion-weightings (b ≥ 10, 000 s/mm2). Quantifying the proportion of this signal (denoted f s ), previously ascertained to originate from inside small spherical spaces, provides a potential proxy for cell body density. In this work, this approach was applied for the first time to a clinical cohort, including patients with diagnosed movement disorders in which the cerebellum has been implicated in symptom pathophysiology. Five control participants (control group 1, median age 24. 5 years (20–39 years), imaged at two timepoints, demonstrated consistency in measurement of all three measures - M D (Mean Diffusivity) f s, and D s (dot diffusivity)- with intraclass correlation coefficients (ICC) of 0. 98, 0. 86 and 0. 76, respectively. Comparison with an older control group (control group 2 (n = 5), median age 51 years (43–58 years)) found no significant differences, neither with morphometric nor microstructural ( M D (p = 0. 36), f s (p = 0. 17) and D s (p = 0. 22)) measures. The movement disorder cohort (Parkinson’s Disease, n = 5, dystonia, n = 5. Spinocerebellar Ataxia 6, n = 5) when compared to the age-matched control cohort (Control Group 2) identified significantly lower MD (p < 0. 0001 and p < 0. 0001) and higher f s values (p < 0. 0001 and p < 0. 0001) in SCA6 and dystonia cohorts respectively. Lobar division of the cerebellum found these same differences in the superior and inferior posterior lobes, while no differences were seen in either the anterior lobes or with D s measurements. In contrast to more conventional measures from diffusion tensor imaging, this framework provides enhanced specificity to differences in restricted spherical spaces in grey matter (including small cells) by eliminating signals from cerebrospinal fluid and axons. In the context of human and animal histopathology studies, these findings potentially implicate the cerebellar Purkinje and granule cells as contributors to the observed signal differences, with both cell types having been implicated in several neurological disorders through both postmortem and animal model studies. This novel microstructural imaging approach shows promise for improving movement disorder diagnosis, prognosis, and treatment.

YNICL Journal 2022 Journal Article

Histogram analysis of tensor-valued diffusion MRI in meningiomas: Relation to consistency, histological grade and type

Jan Brabec
Filip Szczepankiewicz
Finn Lennartsson
Elisabet Englund
Houman Pebdani
Johan Bengzon
Linda Knutsson
Carl-Fredrik Westin

BACKGROUND: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach. PURPOSE: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type. MATERIALS AND METHODS: ). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis. RESULTS: ). CONCLUSION: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.

YNIMG Journal 2021 Journal Article

Accuracy and precision in super-resolution MRI: Enabling spherical tensor diffusion encoding at ultra-high b-values and high resolution

Geraline Vis
Markus Nilsson
Carl-Fredrik Westin
Filip Szczepankiewicz

Diffusion MRI (dMRI) can probe the tissue microstructure but suffers from low signal-to-noise ratio (SNR) whenever high resolution is combined with high diffusion encoding strengths. Low SNR leads to poor precision as well as poor accuracy of the diffusion-weighted signal; the latter is caused by the rectified noise floor and can be observed as a positive bias in magnitude signal. Super-resolution techniques may facilitate a beneficial tradeoff between bias and resolution by allowing acquisition at low spatial resolution and high SNR, whereafter high spatial resolution is recovered by image reconstruction. In this work, we describe a super-resolution reconstruction framework for dMRI and investigate its performance with respect to signal accuracy and precision. Using phantom experiments and numerical simulations, we show that the super-resolution approach improves accuracy by facilitating a more beneficial trade-off between spatial resolution and diffusion encoding strength before the noise floor affects the signal. By contrast, precision is shown to have a less straightforward dependency on acquisition, reconstruction, and intrinsic tissue parameters. Indeed, we find a gain in precision from super-resolution reconstruction is substantial only when some spatial resolution is sacrificed. Finally, we deployed super-resolution reconstruction in a healthy brain for the challenging combination of spherical b-tensor encoding at ultra-high b-values and high spatial resolution-a configuration that produces a unique contrast that emphasizes tissue in which diffusion is restricted in all directions. This demonstration showcased that super-resolution reconstruction enables a vastly superior image contrast compared to conventional imaging, facilitating investigations that would otherwise have prohibitively low SNR, resolution or require non-conventional MRI hardware.

YNIMG Journal 2021 Journal Article

Neural networks for parameter estimation in microstructural MRI: Application to a diffusion-relaxation model of white matter

João P. de Almeida Martins
Markus Nilsson
Björn Lampinen
Marco Palombo
Peter T. While
Carl-Fredrik Westin
Filip Szczepankiewicz

Specific features of white matter microstructure can be investigated by using biophysical models to interpret relaxation-diffusion MRI brain data. Although more intricate models have the potential to reveal more details of the tissue, they also incur time-consuming parameter estimation that may converge to inaccurate solutions due to a prevalence of local minima in a degenerate fitting landscape. Machine-learning fitting algorithms have been proposed to accelerate the parameter estimation and increase the robustness of the attained estimates. So far, learning-based fitting approaches have been restricted to microstructural models with a reduced number of independent model parameters where dense sets of training data are easy to generate. Moreover, the degree to which machine learning can alleviate the degeneracy problem is poorly understood. For conventional least-squares solvers, it has been shown that degeneracy can be avoided by acquisition with optimized relaxation-diffusion-correlation protocols that include tensor-valued diffusion encoding. Whether machine-learning techniques can offset these acquisition requirements remains to be tested. In this work, we employ artificial neural networks to vastly accelerate the parameter estimation for a recently introduced relaxation-diffusion model of white matter microstructure. We also develop strategies for assessing the accuracy and sensitivity of function fitting networks and use those strategies to explore the impact of the acquisition protocol. The developed learning-based fitting pipelines were tested on relaxation-diffusion data acquired with optimal and sub-optimal acquisition protocols. Networks trained with an optimized protocol were observed to provide accurate parameter estimates within short computational times. Comparing neural networks and least-squares solvers, we found the performance of the former to be less affected by sub-optimal protocols; however, model fitting networks were still susceptible to degeneracy issues and their use could not fully replace a careful design of the acquisition protocol.

YNIMG Journal 2021 Journal Article

On the generalizability of diffusion MRI signal representations across acquisition parameters, sequences and tissue types: Chronicles of the MEMENTO challenge

Alberto de Luca
Andrada Ianus
Alexander Leemans
Marco Palombo
Noam Shemesh
Hui Zhang
Daniel C. Alexander
Markus Nilsson

Diffusion MRI (dMRI) has become an invaluable tool to assess the microstructural organization of brain tissue. Depending on the specific acquisition settings, the dMRI signal encodes specific properties of the underlying diffusion process. In the last two decades, several signal representations have been proposed to fit the dMRI signal and decode such properties. Most methods, however, are tested and developed on a limited amount of data, and their applicability to other acquisition schemes remains unknown. With this work, we aimed to shed light on the generalizability of existing dMRI signal representations to different diffusion encoding parameters and brain tissue types. To this end, we organized a community challenge - named MEMENTO, making available the same datasets for fair comparisons across algorithms and techniques. We considered two state-of-the-art diffusion datasets, including single-diffusion-encoding (SDE) spin-echo data from a human brain with over 3820 unique diffusion weightings (the MASSIVE dataset), and double (oscillating) diffusion encoding data (DDE/DODE) of a mouse brain including over 2520 unique data points. A subset of the data sampled in 5 different voxels was openly distributed, and the challenge participants were asked to predict the remaining part of the data. After one year, eight participant teams submitted a total of 80 signal fits. For each submission, we evaluated the mean squared error, the variance of the prediction error and the Bayesian information criteria. The received submissions predicted either multi-shell SDE data (37%) or DODE data (22%), followed by cartesian SDE data (19%) and DDE (18%). Most submissions predicted the signals measured with SDE remarkably well, with the exception of low and very strong diffusion weightings. The prediction of DDE and DODE data seemed more challenging, likely because none of the submissions explicitly accounted for diffusion time and frequency. Next to the choice of the model, decisions on fit procedure and hyperparameters play a major role in the prediction performance, highlighting the importance of optimizing and reporting such choices. This work is a community effort to highlight strength and limitations of the field at representing dMRI acquired with trending encoding schemes, gaining insights into how different models generalize to different tissue types and fiber configurations over a large range of diffusion encodings.

YNIMG Journal 2021 Journal Article

SPHERIOUSLY? The challenges of estimating sphere radius non-invasively in the human brain from diffusion MRI

Maryam Afzali
Markus Nilsson
Marco Palombo
Derek K Jones

The Soma and Neurite Density Imaging (SANDI) three-compartment model was recently proposed to disentangle cylindrical and spherical geometries, attributed to neurite and soma compartments, respectively, in brain tissue. There are some recent advances in diffusion-weighted MRI signal encoding and analysis (including the use of multiple so-called 'b-tensor' encodings and analysing the signal in the frequency-domain) that have not yet been applied in the context of SANDI. In this work, using: (i) ultra-strong gradients; (ii) a combination of linear, planar, and spherical b-tensor encodings; and (iii) analysing the signal in the frequency domain, three main challenges to robust estimation of sphere size were identified: First, the Rician noise floor in magnitude-reconstructed data biases estimates of sphere properties in a non-uniform fashion. It may cause overestimation or underestimation of the spherical compartment size and density. This can be partly ameliorated by accounting for the noise floor in the estimation routine. Second, even when using the strongest diffusion-encoding gradient strengths available for human MRI, there is an empirical lower bound on the spherical signal fraction and radius that can be detected and estimated robustly. For the experimental setup used here, the lower bound on the sphere signal fraction was approximately 10%. We employed two different ways of establishing the lower bound for spherical radius estimates in white matter. The first, examining power-law relationships between the DW-signal and diffusion weighting in empirical data, yielded a lower bound of 7μm, while the second, pure Monte Carlo simulations, yielded a lower limit of 3μm and in this low radii domain, there is little differentiation in signal attenuation. Third, if there is sensitivity to the transverse intra-cellular diffusivity in cylindrical structures, e.g., axons and cellular projections, then trying to disentangle two diffusion-time-dependencies using one experimental parameter (i.e., change in frequency-content of the encoding waveform) makes spherical radii estimates particularly challenging. We conclude that due to the aforementioned challenges spherical radii estimates may be biased when the corresponding sphere signal fraction is low, which must be considered.

YNIMG Journal 2020 Journal Article

Improved fibre dispersion estimation using b-tensor encoding

Michiel Cottaar
Filip Szczepankiewicz
Matteo Bastiani
Moises Hernandez-Fernandez
Stamatios N. Sotiropoulos
Markus Nilsson
Saad Jbabdi

Measuring fibre dispersion in white matter with diffusion magnetic resonance imaging (MRI) is limited by an inherent degeneracy between fibre dispersion and microscopic diffusion anisotropy (i. e. , the diffusion anisotropy expected for a single fibre orientation). This means that estimates of fibre dispersion rely on strong assumptions, such as constant microscopic anisotropy throughout the white matter or specific biophysical models. Here we present a simple approach for resolving this degeneracy using measurements that combine linear (conventional) and spherical tensor diffusion encoding. To test the accuracy of the fibre dispersion when our microstructural model is only an approximation of the true tissue structure, we simulate multi-compartment data and fit this with a single-compartment model. For such overly simplistic tissue assumptions, we show that the bias in fibre dispersion is greatly reduced (~5x) for single-shell linear and spherical tensor encoding data compared with single-shell or multi-shell conventional data. In in-vivo data we find a consistent estimate of fibre dispersion as we reduce the b-value from 3 to 1. 5 m s / μ m 2, increase the repetition time, increase the echo time, or increase the diffusion time. We conclude that the addition of spherical tensor encoded data to conventional linear tensor encoding data greatly reduces the sensitivity of the estimated fibre dispersion to the model assumptions of the tissue microstructure.

YNIMG Journal 2020 Journal Article

The dot-compartment revealed? Diffusion MRI with ultra-strong gradients and spherical tensor encoding in the living human brain

Chantal M.W. Tax
Filip Szczepankiewicz
Markus Nilsson
Derek K. Jones

The so-called “dot-compartment” is conjectured in diffusion MRI to represent small spherical spaces, such as cell bodies, in which the diffusion is restricted in all directions. Previous investigations inferred its existence from data acquired with directional diffusion encoding which does not permit a straightforward separation of signals from ‘sticks’ (axons) and signals from ‘dots’. Here we combine isotropic diffusion encoding with ultra-strong diffusion gradients (240 mT/m) to achieve high diffusion-weightings with high signal to noise ratio, while suppressing signal arising from anisotropic water compartments with significant mobility along at least one axis (e. g. , axons). A dot-compartment, defined to have apparent diffusion coefficient equal to zero and no exchange, would result in a non-decaying signal at very high b-values ( b ≳ 7000 s/mm 2 ). With this unique experimental setup, a residual yet slowly decaying signal above the noise floor for b-values as high as 15000 s/mm 2 was seen clearly in the cerebellar grey matter (GM), and in several white matter (WM) regions to some extent. Upper limits of the dot-signal-fraction were estimated to be 1. 8% in cerebellar GM and 0. 5% in WM. By relaxing the assumption of zero diffusivity, the signal at high b-values in cerebellar GM could be represented more accurately by an isotropic water pool with a low apparent diffusivity of 0. 12 μm 2 / ms and a substantial signal fraction of 9. 7%. The T2 of this component was estimated to be around 61 ms. This remaining signal at high b-values has potential to serve as a novel and simple marker for isotropically-restricted water compartments in cerebellar GM.

YNIMG Journal 2018 Journal Article

Imaging brain tumour microstructure

Markus Nilsson
Elisabet Englund
Filip Szczepankiewicz
Danielle van Westen
Pia C. Sundgren

Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called ‘microstructure imaging’. The promise of microstructure imaging is one of ‘virtual biopsy’ with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging.

YNIMG Journal 2017 Journal Article

Neurite density imaging versus imaging of microscopic anisotropy in diffusion MRI: A model comparison using spherical tensor encoding

Björn Lampinen
Filip Szczepankiewicz
Johan Mårtensson
Danielle van Westen
Pia C. Sundgren
Markus Nilsson

In diffusion MRI (dMRI), microscopic diffusion anisotropy can be obscured by orientation dispersion. Separation of these properties is of high importance, since it could allow dMRI to non-invasively probe elongated structures such as neurites (axons and dendrites). However, conventional dMRI, based on single diffusion encoding (SDE), entangles microscopic anisotropy and orientation dispersion with intra-voxel variance in isotropic diffusivity. SDE-based methods for estimating microscopic anisotropy, such as the neurite orientation dispersion and density imaging (NODDI) method, must thus rely on model assumptions to disentangle these features. An alternative approach is to directly quantify microscopic anisotropy by the use of variable shape of the b-tensor. Along those lines, we here present the ‘constrained diffusional variance decomposition’ (CODIVIDE) method, which jointly analyzes data acquired with diffusion encoding applied in a single direction at a time (linear tensor encoding, LTE) and in all directions (spherical tensor encoding, STE). We then contrast the two approaches by comparing neurite density estimated using NODDI with microscopic anisotropy estimated using CODIVIDE. Data were acquired in healthy volunteers and in glioma patients. NODDI and CODIVIDE differed the most in gray matter and in gliomas, where NODDI detected a neurite fraction higher than expected from the level of microscopic diffusion anisotropy found with CODIVIDE. The discrepancies could be explained by the NODDI tortuosity assumption, which enforces a connection between the neurite density and the mean diffusivity of tissue. Our results suggest that this assumption is invalid, which leads to a NODDI neurite density that is inconsistent between LTE and STE data. Using simulations, we demonstrate that the NODDI assumptions result in parameter bias that precludes the use of NODDI to map neurite density. With CODIVIDE, we found high levels of microscopic anisotropy in white matter, intermediate levels in structures such as the thalamus and the putamen, and low levels in the cortex and in gliomas. We conclude that accurate mapping of microscopic anisotropy requires data acquired with variable shape of the b-tensor.

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.

YNIMG Journal 2016 Journal Article

The link between diffusion MRI and tumor heterogeneity: Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE)

Filip Szczepankiewicz
Danielle van Westen
Elisabet Englund
Carl-Fredrik Westin
Freddy Ståhlberg
Jimmy Lätt
Pia C. Sundgren
Markus Nilsson

The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MKT), and DIVIDE was used to decompose MKT into components caused by microscopic anisotropy (MKA) and isotropic heterogeneity (MKI). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (μFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MKA correlated with cell eccentricity (r =0. 95, p <10−7) and MKI with the cell density variance (r =0. 83, p <10−3). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r =0. 80, p <10−3) and microscopic scale (μFA, r =0. 93, p <10−6). A multiple regression analysis showed that the conventional MKT parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MKA was associated only to cell eccentricity, and MKI only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean±s. d.) MKA =1. 11±0. 33 vs MKI =0. 44±0. 20 (p <10−3), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MKI =0. 57±0. 30 vs MKA =0. 26±0. 11 (p <0. 05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale.

YNIMG Journal 2015 Journal Article

Quantification of microscopic diffusion anisotropy disentangles effects of orientation dispersion from microstructure: Applications in healthy volunteers and in brain tumors

Filip Szczepankiewicz
Samo Lasič
Danielle van Westen
Pia C. Sundgren
Elisabet Englund
Carl-Fredrik Westin
Freddy Ståhlberg
Jimmy Lätt

The anisotropy of water diffusion in brain tissue is affected by both disease and development. This change can be detected using diffusion MRI and is often quantified by the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Although FA is sensitive to anisotropic cell structures, such as axons, it is also sensitive to their orientation dispersion. This is a major limitation to the use of FA as a biomarker for “tissue integrity”, especially in regions of complex microarchitecture. In this work, we seek to circumvent this limitation by disentangling the effects of microscopic diffusion anisotropy from the orientation dispersion. The microscopic fractional anisotropy (μFA) and the order parameter (OP) were calculated from the contrast between signal prepared with directional and isotropic diffusion encoding, where the latter was achieved by magic angle spinning of the q-vector (qMAS). These parameters were quantified in healthy volunteers and in two patients; one patient with meningioma and one with glioblastoma. Finally, we used simulations to elucidate the relation between FA and μFA in various micro-architectures. Generally, μFA was high in the white matter and low in the gray matter. In the white matter, the largest differences between μFA and FA were found in crossing white matter and in interfaces between large white matter tracts, where μFA was high while FA was low. Both tumor types exhibited a low FA, in contrast to the μFA which was high in the meningioma and low in the glioblastoma, indicating that the meningioma contained disordered anisotropic structures, while the glioblastoma did not. This interpretation was confirmed by histological examination. We conclude that FA from DTI reflects both the amount of diffusion anisotropy and orientation dispersion. We suggest that the μFA and OP may complement FA by independently quantifying the microscopic anisotropy and the level of orientation coherence.

YNIMG Journal 2013 Journal Article

Variability in diffusion kurtosis imaging: Impact on study design, statistical power and interpretation

Filip Szczepankiewicz
Jimmy Lätt
Ronnie Wirestam
Alexander Leemans
Pia Sundgren
Danielle van Westen
Freddy Ståhlberg
Markus Nilsson

Diffusion kurtosis imaging (DKI) is an emerging technique with the potential to quantify properties of tissue microstructure that may not be observable using diffusion tensor imaging (DTI). In order to help design DKI studies and improve interpretation of DKI results, we employed statistical power analysis to characterize three aspects of variability in four DKI parameters; the mean diffusivity, fractional anisotropy, mean kurtosis, and radial kurtosis. First, we quantified the variability in terms of the group size required to obtain a statistical power of 0. 9. Second, we investigated the relative contribution of imaging and post-processing noise to the total variance, in order to estimate the benefits of longer scan times versus the inclusion of more subjects. Third, we evaluated the potential benefit of including additional covariates such as the size of the structure when testing for differences in group means. The analysis was performed in three major white matter structures of the brain: the superior cingulum, the corticospinal tract, and the mid-sagittal corpus callosum, extracted using diffusion tensor tractography and DKI data acquired in a healthy cohort. The results showed heterogeneous variability across and within the white matter structures. Thus, the statistical power varies depending on parameter and location, which is important to consider if a pathogenesis pattern is inferred from DKI data. In the data presented, inter-subject differences contributed more than imaging noise to the total variability, making it more efficient to include more subjects rather than extending the scan-time per subject. Finally, strong correlations between DKI parameters and the structure size were found for the cingulum and corpus callosum. Structure size should thus be considered when quantifying DKI parameters, either to control for its potentially confounding effect, or as a means of reducing unexplained variance.

AIIM Journal 2006 Journal Article

Clinical decision-support for diagnosing stress-related disorders by applying psychophysiological medical knowledge to an instance-based learning system

Markus Nilsson
Peter Funk
Erik M.G. Olsson
Bo von Schéele
Ning Xiong

Objective An important procedure in diagnosing stress-related disorders caused by dysfunction in the interaction of the heart with breathing, i. e. , respiratory sinus arrhythmia (RSA), is to analyse the breathing first and then the heart rate. Analysing these measurements is a time-consuming task for the diagnosing clinician. A decision-support system in this area would reduce the analysis task of the clinician and enable him/her to give more attention to the patient. We have created a decision-support system which contains a signal classifier and a pattern identifier. The system performs an analysis of the physiological time series concerned which would otherwise be performed manually by the clinician. Methods The signal-classifier, HR3Modul, classifies heart-rate patterns by analysing both cardio- and pulmonary signals, i. e. , physiological time series. HR3Modul uses case-based reasoning (CBR), using a wavelet-based method for retrieving features from the signals. The system searches for familiar shapes in the signals by comparing them with shapes already stored. We have applied a best fit scheme for handling signals of different lengths, as the length of a breath is highly dynamic. We also apply automatic weighting to the features to obtain a more autonomous system. The classified heart signals indicate if a patient may be suffering from a stress-related disorder and the nature of the disorder. These classified signals are thereafter sent to the second subsystem, the pattern-identifier. The pattern-identifier analyses the classified signals and searches for familiar patterns by identifying sequences in the classified signals. The identified sequences give clinicians a more complete analysis of the measurements, providing them with a better basis for diagnosis. Results and conclusion We have shown that a case-based classifier with a wavelet feature extractor and automatic weighting is a viable option for building a decision-support system for the psychophysiological domain, as it is at par, or even outperforms other retrieval techniques and is less complex.