Fuzzy Fibers: Uncertainty in dMRI Tractography

Fiber tracking based on diffusion weighted Magnetic Resonance Imaging (dMRI) allows for noninvasive reconstruction of fiber bundles in the human brain. In this chapter, we discuss sources of error and uncertainty in this technique, and review strategies that afford a more reliable interpretation of the results. This includes methods for computing and rendering probabilistic tractograms, which estimate precision in the face of measurement noise and artifacts. However, we also address aspects that have received less attention so far, such as model selection, partial voluming, and the impact of parameters, both in preprocessing and in fiber tracking itself. We conclude by giving impulses for future research

Test-retest reliability of structural brain networks from diffusion MRI

Structural brain networks constructed from diffusion MRI (dMRI) and tractography have been demonstrated in healthy volunteers and more recently in various disorders affecting brain connectivity. However, few studies have addressed the reproducibility of the resulting networks. We measured the test–retest properties of such networks by varying several factors affecting network construction using ten healthy volunteers who underwent a dMRI protocol at 1.5 T on two separate occasions. Each T1-weighted brain was parcellated into 84 regions-of-interest and network connections were identified using dMRI and two alternative tractography algorithms, two alternative seeding strategies, a white matter waypoint constraint and three alternative network weightings. In each case, four common graph-theoretic measures were obtained. Network properties were assessed both node-wise and per network in terms of the intraclass correlation coefficient (ICC) and by comparing within- and between-subject differences. Our findings suggest that test–retest performance was improved when: 1) seeding from white matter, rather than grey; and 2) using probabilistic tractography with a two-fibre model and sufficient streamlines, rather than deterministic tensor tractography. In terms of network weighting, a measure of streamline density produced better test–retest performance than tract-averaged diffusion anisotropy, although it remains unclear which is a more accurate representation of the underlying connectivity. For the best performing configuration, the global within-subject differences were between 3.2% and 11.9% with ICCs between 0.62 and 0.76. The mean nodal within-subject differences were between 5.2% and 24.2% with mean ICCs between 0.46 and 0.62. For 83.3% (70/84) of nodes, the within-subject differences were smaller than between-subject differences. Overall, these findings suggest that whilst current techniques produce networks capable of characterising the genuine between-subject differences in connectivity, future work must be undertaken to improve network reliability

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T1-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24–43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24–47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection

Optic radiation structure and anatomy in the normally developing brain determined using diffusion MRI and tractography

The optic radiation (OR) is a component of the visual system known to be myelin mature very early in life. Diffusion tensor imaging (DTI) and its unique ability to reconstruct the OR in vivo were used to study structural maturation through analysis of DTI metrics in a cohort of 90 children aged 5–18 years. As the OR is at risk of damage during epilepsy surgery, we measured its position relative to characteristic anatomical landmarks. Anatomical distances, DTI metrics and volume of the OR were investigated for age, gender and hemisphere effects. We observed changes in DTI metrics with age comparable to known trajectories in other white matter tracts. Left lateralization of DTI metrics was observed that showed a gender effect in lateralization. Sexual dimorphism of DTI metrics in the right hemisphere was also found. With respect to OR dimensions, volume was shown to be right lateralised and sexual dimorphism demonstrated for the extent of the left OR. The anatomical results presented for the OR have potentially important applications for neurosurgical planning

White Matter Structural Connectivity is Associated with Sensorimotor Function in Stroke Survivors

Purpose Diffusion tensor imaging (DTI) provides functionally relevant information about white matter structure. Local anatomical connectivity information combined with fractional anisotropy (FA) and mean diffusivity (MD) may predict functional outcomes in stroke survivors. Imaging methods for predicting functional outcomes in stroke survivors are not well established. This work uses DTI to objectively assess the effects of a stroke lesion on white matter structure and sensorimotor function. Methods A voxel-based approach is introduced to assess a stroke lesion\u27s global impact on motor function. Anatomical T1-weighted and diffusion tensor images of the brain were acquired for nineteen subjects (10 post-stroke and 9 age-matched controls). A manually selected volume of interest was used to alleviate the effects of stroke lesions on image registration. Images from all subjects were registered to the images of the control subject that was anatomically closest to Talairach space. Each subject\u27s transformed image was uniformly seeded for DTI tractography. Each seed was inversely transformed into the individual subject space, where DTI tractography was conducted and then the results were transformed back to the reference space. A voxel-wise connectivity matrix was constructed from the fibers, which was then used to calculate the number of directly and indirectly connected neighbors of each voxel. A novel voxel-wise indirect structural connectivity (VISC) index was computed as the average number of direct connections to a voxel\u27s indirect neighbors. Voxel-based analyses (VBA) were performed to compare VISC, FA, and MD for the detection of lesion-induced changes in sensorimotor function. For each voxel, a t-value was computed from the differences between each stroke brain and the 9 controls. A series of linear regressions was performed between Fugl-Meyer (FM) assessment scores of sensorimotor impairment and each DTI metric\u27s log number of voxels that differed from the control group. Results Correlation between the logarithm of the number of significant voxels in the ipsilesional hemisphere and total Fugl-Meyer score was moderate for MD (R2 = 0.512), and greater for VISC (R2 = 0.796) and FA (R2 = 0.674). The slopes of FA (p = 0.0036), VISC (p = 0.0005), and MD (p = 0.0199) versus the total FM score were significant. However, these correlations were driven by the upper extremity motor component of the FM score (VISC: R2 = 0.879) with little influence of the lower extremity motor component (FA: R2 = 0.177). Conclusion The results suggest that a voxel-wise metric based on DTI tractography can predict upper extremity sensorimotor function of stroke survivors, and that supraspinal intraconnectivity may have a less dominant role in lower extremity function

Reproducibility and sensitivity of brain network backbones: a demonstration in Small Vessel Disease

Mestrado integrado em Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas) Universidade de Lisboa; Faculdade de Ciências, 2020Whole-brain networks have been used to study the connectivity paths within the brain, constructed using information from diffusion magnetic resonance imaging (dMRI) data and white matter fiber tractography (FT). These techniques can detect alterations in the white matter integrity and changes in axonal connections, whose alterations can be due to the presence of small vessel disease (SVD). However, there is a lack of consensus in network reconstruction methods and therefore no gold-standard model of the human brain network. Moreover, dMRI data are affected by methodological issues such as scan noise, presence of false-positive and false-negative connections. Consequently, the reproducibility and the reliability of these networks is normally very low. A potential solution to deal with the low reproducibility of brain networks is to analyze only its backbone structure. This backbone is assumed to represent the building blocks of structural brain networks and thus composed by a set of strong connections and voided of spurious connections. Such backbone should be reproducible in scan-rescan scenarios and relatively consistent between healthy subjects, while still being sensitive to disease-related changes. Several types of backbones have been proposed, constructed using white matter tractography, with dMRI data. However, no study has directly compared these backbones in terms of reproducibility, consistency, or sensitivity to disease effects in a patient population. In this project, we examined: (1) whether the proposed backbones can be applied to clinical datasets by testing if they are reproducible over two time-points and consistent between groups; (2) if they are sensitive to disease effects both in a cross-sectional and longitudinal analysis. We evaluated our research questions on a longitudinal cohort of patients with cerebral SVD and age matched controls, as well as a validation dataset of healthy young adults. Our cohort contained 87 elderly memory clinic patients with SVD recruited via the UMC Utrecht, scanned twice with an inter-scan time between baseline and follow-up of 27 ± 4 months. We also included baseline scans of 45 healthy elderly, matched in age, sex and education level, to be used as controls. Data from 44 healthy young adults was used as validation data. For each subject, we reconstructed brain structural networks from the diffusion MRI data. Subsequently, we computed 4 types of network backbone, previously described in literature: the Minimal Spanning Tree (MST), the Disparity Core, the K-Core, and Hub-Core. We compared these backbones and tested their reproducibility within subjects, and their consistency across subjects and across groups. Moreover, we performed a cross-sectional analysis between controls and patients at baseline, to evaluate if these backbones can detect disease effects and a longitudinal analysis with patient data over time, to test if they can detect disease progression. Regarding our first objective, our results show that overall MST is the backbone that shows the best reproducibility between repeated scans, as well as the highest consistency among subjects, for all of the three brain templates that we used. Secondly, the MST was also sensitive to network alterations both on a cross-sectional analysis (patients vs. controls) and on a longitudinal analysis (baseline vs. follow-up). We therefore conclude that, the use of these network backbones, as an alternative of the whole-brain network analysis, can successfully be applied to clinical datasets as a novel and reliable way to detect disease effects and evaluate disease progression.A demência vascular cerebral (SVD) é a segunda principal causa de demência, depois da doença de Alzheimer. Este tipo de demência está relacionado com patologias vasculares cerebrais, assim como com perda de funcionalidades cognitivas. Vários estudos explicam que a degradação da atividade cognitiva característica desta doença pode dever-se à diminuição da integridade da substância branca e a alterações nas conexões axonais. O estudo da conectividade cerebral tem sido uma forte aposta no estudo das causas e da forma como a demência vascular cerebral evolui. A construção de mapas neuronais é uma das práticas que mais tem sido usada para estudar e entender os mecanismos principais da conectividade cerebral: representar o cérebro como um conjunto de regiões e as ligações entre elas. Para isso, utiliza-se informação proveniente de imagens de ressonância magnética por difusão (dMRI), especificamente de imagens por tensor de difusão (DTI), capazes de medir a magnitude de difusão das moléculas de água no cérebro in vivo, através de gradientes aplicados em pelo menos seis direções no espaço. Desta forma, é possível estimar a direção principal do movimento das moléculas de água que compõem as microfibras da substância branca cerebral, e reconstruir os percursos de neurónios que conectam as várias regiões do cérebro. Este processo é chamado de tractografia de fibras (FT), que proporciona um modelo a três dimensões da arquitetura tecidular cerebral, permitindo a visualização e o estudo da conectividade e da continuidade dos percursos neuronais. Assim, é possível obter informação quantitativa acerca do sistema nervoso in vivo e contruir mapas de conectividade cerebral. No entanto, existe falta de consenso sobre as regras de reconstrução destes mapas neuronais, fazendo com que não haja um modelo-base para o estudo dos mesmos. Além disto, os dados provenientes das imagens de dMRI são facilmente afetados e podem diferir da realidade. Alguns exemplos mais comuns são a presença de ruído e existência tanto de conexões falsas como a ausência de conexões que deviam estar presentes, chamadas respetivamente de falsos-positivos e falsos-negativos. Consequentemente, os modelos de conectividade não podem ser comparados entre diferentes aparelhos de ressonância, nem mesmo entre diferentes momentos temporais, por terem uma baixa reprodutibilidade, tornando estes métodos poucos fiáveis. As soluções propostas para lidar com esta falta de consenso quanto à reconstrução de mapas ou redes neuronais e a presença de conexões falsas podem ser agrupadas em duas categorias: normalização e redução da rede neuronal através da aplicação de um limiar (threshold, em inglês). Contudo, os processos de normalização para remover certas tendências erradas destas redes não eram suficientes e, por vezes, introduziam outras dependências. Quanto à aplicação de limiares, mesmo que alguns estudos mostrem que a sua utilização no mapa neuronal do cérebro todo pode efetivamente eliminar alguns efeitos, a própria escolha de um limiar pode conduzir a modificações nas redes neuronais através de eliminação de certas comunicações fundamentais. Como uma extensão da redução destas redes neuronais com o objetivo de lidar com a sua baixa reprodutibilidade, vários estudos têm proposto uma nova abordagem: analisar apenas uma espécie de esqueleto das mesmas. O objetivo deste “esqueleto-neuronal” é o de representar as ligações mais importantes e estruturais e estar isento de falsas conexões. Idealmente, este “esqueleto-neuronal” seria reprodutível entre diferentes dispositivos e consistente entre indivíduos saudáveis, enquanto se manteria fiel às diferenças causadas pela presença de doenças. Assim sendo, o estudo da extração de um esqueleto-neuronal, visa encontrar estruturas fundamentais que evitem a perda de propriedades topológicas. Por exemplo, considerando pacientes com SVD, estes esqueletos-neuronais devem fornecer uma melhor compreensão das alterações da conectividade cerebral ao longo do tempo, permitindo uma comparação sólida entre diferentes pontos no tempo e a identificação de alterações que sejam consequência inegável de doença. Alguns tipos destas redes neuronais foram já propostos em diversas publicações científicas, que podem ser construídos utilizando FT de substância branca com informação proveniente de dMRI. Neste estudo, utilizamos o Minimum Spanning Tree (MST), o K-Core, o Disparity Core e o Hub-Core, que são redes-esqueleto já existentes na literatura. A eficácia tanto do uso do MST como do K-Core já foram comprovadas tanto a nível de deteção de alterações da conectividade cerebral, como na medida em que conseguem manter as conexões mais importantes do esqueleto cerebral, eliminando conexões que podem ser consideradas duvidosas. No entanto, até agora, nenhum estudo se focou na comparação dos diferentes esqueletos-neuronais existentes quanto à sua reproducibilidade, consistência ou sensibilidade aos efeitos de doença ao longo do tempo. Neste estudo, utilizamos os quatro modelos-esqueletos mencionados anteriormente, avaliando: (1) se estes esqueletos-neuronais podem ser efetivamente aplicados a dados clínicos, testando a sua reproducibilidade entre dois pontos de tempos distintos e a sua consistência entre grupos de controlos saudáveis; (2) se são sensíveis a efeitos causados por doença, tanto entre controlos e pacientes, como na evolução de alterações de conectividade em pacientes ao longo do tempo. Os dados longitudinais utilizados provêm de imagens ponderadas em T1 de 87 pacientes idosos com SVD, assim como de um grupo controlo de 45 idosos saudáveis coincidentes em idade com estes pacientes, e de um grupo de validação constituído por 44 jovens saudáveis. Para cada um dos objetivos, testamos os 4 tipos de esqueletos-neuronais, baseados primeiramente num modelo que divide o córtex cerebral em 90 regiões de interesse (ROIs) e posteriormente em modelos de 200 e 250 regiões. No pós-processamento, foram construídas e comparadas matrizes de conectividade que representam as ligações entre as várias regiões em que dividimos o córtex. Com estas matrizes foi possível calcular valores de conectividade como a força nodal (NS) e a eficiência global (GE). Também foram comparadas matrizes que diziam respeito a parâmetros específicos de DTI como a anisotropia fracionada (FA) e a difusividade média (MD). A análise estatística foi feita utilizando testes paramétricos t-test e ANOVA. Os resultados indicam que, no geral, estas redes podem ser utilizadas como forma de analisar e estudar mapas de conectividade cerebral de forma mais precisa, pois são reprodutíveis entre controlos saudáveis em tempos diferentes, e conseguem detetar as diferenças de conectividade devidas a doença. Além disso, representam as ligações mais importantes da rede de conectividade neuronal, criando uma base para comparações fiáveis. A maior parte dos esqueletos-neuronais mostraram ser consistentes dentro de cada grupo de estudo, e apresentaram diferenças de conectividade entre controlos e pacientes. Neste caso, comparando sujeitos saudáveis com pacientes, os valores das componentes de FA e de MD destes esqueletos neuronais, e as suas alterações, vão de encontro com a literatura sobre a evolução do estado das ligações neuronais no desenvolvimento de demência. Quanto à análise longitudinal dos pacientes, concluímos que a NS representa uma medida mais fiável de análise das alterações ao longo do tempo da doença do que a GE. Finalmente, e ainda que algumas destes esqueletos-neuronais tenham mostrado melhor desempenho do que outros em diferentes abordagens, concluímos que o MST é a rede-esqueleto que dispõe dos melhores resultados utilizando o modelo de 90 e 200 ROIs, do cérebro todo, assim como usando o modelo de 250 ROIs aplicado só ao hemisfério esquerdo. Em suma, conclui-se que a utilização destes tipos de redes-esqueleto pode vir a tornar-se uma melhor alternativa em relação à utilização das redes neuronais originais do cérebro completo, visto que podem ser eficazmente aplicadas à análise de dados clínicos como forma fiável de detetar presença e evolução de doenças

Tractographic and Microstructural Analysis of the Dentato-Rubro-Thalamo-Cortical Tracts in Children Using Diffusion MRI

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors