Reducing variability in along-tract analysis with diffusion profile realignment

Diffusion weighted MRI (dMRI) provides a non invasive virtual reconstruction of the brain's white matter structures through tractography. Analyzing dMRI measures along the trajectory of white matter bundles can provide a more specific investigation than considering a region of interest or tract-averaged measurements. However, performing group analyses with this along-tract strategy requires correspondence between points of tract pathways across subjects. This is usually achieved by creating a new common space where the representative streamlines from every subject are resampled to the same number of points. If the underlying anatomy of some subjects was altered due to, e.g. disease or developmental changes, such information might be lost by resampling to a fixed number of points. In this work, we propose to address the issue of possible misalignment, which might be present even after resampling, by realigning the representative streamline of each subject in this 1D space with a new method, coined diffusion profile realignment (DPR). Experiments on synthetic datasets show that DPR reduces the coefficient of variation for the mean diffusivity, fractional anisotropy and apparent fiber density when compared to the unaligned case. Using 100 in vivo datasets from the HCP, we simulated changes in mean diffusivity, fractional anisotropy and apparent fiber density. Pairwise Student's t-tests between these altered subjects and the original subjects indicate that regional changes are identified after realignment with the DPR algorithm, while preserving differences previously detected in the unaligned case. This new correction strategy contributes to revealing effects of interest which might be hidden by misalignment and has the potential to improve the specificity in longitudinal population studies beyond the traditional region of interest based analysis and along-tract analysis workflows.Comment: v4: peer-reviewed round 2 v3 : deleted some old text from before peer-review which was mistakenly included v2 : peer-reviewed version v1: preprint as submitted to journal NeuroImag

Evaluating the Reliability of Human Brain White Matter Tractometry

Published Nov 17, 2021The validity of research results depends on the reliability of analysis methods. In recent years, there have been concerns about the validity of research that uses diffusion-weighted MRI (dMRI) to understand human brain white matter connections in vivo, in part based on the reliability of analysis methods used in this field. We defined and assessed three dimensions of reliability in dMRI-based tractometry, an analysis technique that assesses the physical properties of white matter pathways: (1) reproducibility, (2) test-retest reliability, and (3) robustness. To facilitate reproducibility, we provide software that automates tractometry (https://yeatmanlab.github.io/pyAFQ). In measurements from the Human Connectome Project, as well as clinical-grade measurements, we find that tractometry has high test-retest reliability that is comparable to most standardized clinical assessment tools. We find that tractometry is also robust: showing high reliability with different choices of analysis algorithms. Taken together, our results suggest that tractometry is a reliable approach to analysis of white matter connections. The overall approach taken here both demonstrates the specific trustworthiness of tractometry analysis and outlines what researchers can do to establish the reliability of computational analysis pipelines in neuroimaging.This work was supported through grant 1RF1MH121868- 01 from the National Institute of Mental Health/the BRAIN Initiative, through grant 5R01EB027585-02 to Eleftherios Garyfallidis (Indiana University) from the National Institute of Biomedical Imaging and Bioengineering, through Azure Cloud Computing Credits for Research & Teaching provided through the University of Washington’s Research Computing unit and the University of Washington eScience Institute, and NICHD R21HD092771 to Jason D. Yeatma

Anatomo-functional magnetic resonance imaging of the spinal cord and its application to the characterization of spinal lesions in cats

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique.Spinal cord injury has a significant impact on quality of life since it can lead to motor (paralysis) and sensory deficits. These deficits evolve in time as reorganisation of the central nervous system occurs, involving physiological and neurochemical mechanisms that are still not fully understood. Given that both the severity of the deficit and the successful rehabilitation process depend on the anatomical pathways that have been altered in the spinal cord, it may be of great interest to assess white matter integrity after a spinal lesion and to evaluate quantitatively the functional state of spinal neurons. The great potential of magnetic resonance imaging (MRI) lies in its ability to investigate both anatomical and functional properties of the central nervous system non invasively. To address the problem of spinal cord injury, this project aimed to evaluate the benefits of diffusion-weighted MRI to assess the integrity of white matter axons that remain after spinal cord injury. The second objective was to evaluate to what extent functional MRI can measure the activity of neurons in the spinal cord. Although widely applied to the brain, diffusion-weighted MRI and functional MRI of the spinal cord are not straightforward. Various issues arise from the small cross-section width of the cord, the presence of cardiac and respiratory motions, and from magnetic field inhomogeneities in the spinal region. The main purpose of the present thesis was therefore to develop methodologies to circumvent these issues. This development notably focused on the optimization of acquisition parameters to image anatomical, diffusion-weighted and functional data in cats and humans at 3T using standard coils and pulse sequences. Moreover, various strategies to correct for susceptibility-induced distortions were investigated and the sensitivity and specificity in spinal cord functional MRI was studied. As a result, acquisition of high spatial and angular diffusion-weighted images and evaluation of the integrity of specific spinal pathways following spinal cord injury was achieved. Moreover, functional activations in the spinal cord of anaesthetized cats was detected. Although encouraging, these results highlight the need for further technical and methodological development in the near-future. Being able to develop a reliable neuroimaging tool for confirming clinical parameters would improve diagnostic and prognosis. It would also enable to monitor the effect of various therapeutic strategies. This would certainly bring hope to a large number of people suffering from trauma and neurodegenerative diseases such as spinal cord injury, tumours, multiple sclerosis and amyotrophic lateral sclerosis

Characterising population variability in brain structure through models of whole-brain structural connectivity

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender

Neuroimaging of functional and structural alterations in Juvenile Myoclonic Epilepsy and Frontal Lobe Epilepsy

Epilepsy is the commonest neurological disorder and has profound effects on patients, who suffer from epileptic seizures and also from cognitive impairment. The exact mechanisms of cognitive impairment remain unclear. Aim of this study was to analyse in more detail the functional and structural alterations in two different patient groups, juvenile myoclonic epilepsy (JME) and frontal lobe epilepsy (FLE). We recruited and investigated 26 healthy controls, 30 patients with JME and 67 patients with FLE. All participants underwent magnetic resonance imaging (MRI), including structural imaging, five functional MRI paradigms and diffusion tensor imaging (DTI) as well as neuropsychological assessment. In patients with JME we could show motor cortex hyperactivity and an increased functional connectivity between the pre-frontal cognitive cortex and the motor system. This correlated with increased structural connectivity, measured by DTI and also with disease severity: patients with more active epilepsy showed a stronger hyperconnectivity. In FLE, we could show extensive reorganization of cognitive functions, and we could show, that functional MRI can be used as a new diagnostic method, to identify dysfunctional areas, indicative of the seizure onset zone. This is particularly important in patients with nonlesional FLE, where epilepsy surgery may be advisable but is challenged by the absence of a visible surgical target. The study has provided new insights into pathophysiological mechanisms in JME, specifically explaining the characteristic effect of motor seizures triggered by cognitive effort. It has contributed strong evidence that the observed imaging alterations are the cause and not a consequence of JME, by documenting marked structural changes in seizure free patients. For patients with FLE the study showed highly individual effects of chronic epilepsy on cognitive processing in the frontal lobe. These alterations are clinically relevant for both, avoiding complications from surgery, but also to identify pathological alterations not visible in conventional MRI

Lesion identification and the effect of lesion on motor mapping after stroke

Stroke is the most common cause of long-term severe disability and the motor system that is most commonly affected in stroke. One of the mechanisms that underlies recovery of motor deficits is reorganization or remapping of functional representations around the motor cortex. This mechanism has been shown in monkeys, but results in human subjects have been variable. In this thesis, I used a database that includes longitudinal behavioral and multimodal imaging data in both stroke patients and healthy controls for two research projects. Firstly, I improved an automatic lesion segmentation method to aid in the identification of the location and extent of the stroke in structural magnetic resonance imaging (MRI) images. I developed a point and click interface that allows for the automatic segmentation as well as selecting lesions generated at different thresholds based on the contrast of the T1 images. Second, I investigated the effect of subcortical strokes on motor representations by measuring changes in the topography of inter-hemispheric resting state functional connectivity (FC) MRI to track changes of the hand representation in the damaged hemisphere shows a higher variation across the medial-lateral axis, suggesting a shift in neighboring body representations along the motor strip. During recovery, however, there is a shift in an anterior-posterior direction suggesting a shift into sensory and premotor regions. Obtaining lesion profile and understanding its effect on the functional connectivity can provide us with useful information on the effects of stroke on brain structure and function, which in turn will help in the prognosis and rehabilitation of stroke patients

The contribution of brain reorganisation to recovery in patients with optic neuritis

In this thesis, the mechanisms of damage and repair in clinically isolated optic neuritis (ON) were investigated in vivo, by combining magnetic resonance imaging (MRI), electrophysiology and optical coherence tomography (OCT). ON is a demyelinating, inflammatory condition of the optic nerve, which may be the first presentation of multiple sclerosis. The visual prognosis is generally good, despite optic nerve demyelination and axonal loss, but some patients fail to recover. The aim of this thesis was to determine the reasons underlying recovery. The hypothesis was that neuroplastic grey matter reorganisation might contribute to visual outcome. Structural MRI, electrophysiology and OCT were used to quantify optic nerve oedema, inflammation, myelination and neuroaxonal loss, and optic radiation and visual cortical pathology, in a cohort of patients with acute ON, followed up over the following year. Visual functional MRI (fMRI) was employed to investigate neuroplasticity. Acutely, measures of optic nerve inflammation and conduction block were associated with the severity of acute visual loss, and were used to inform an fMRI analysis, in order to dissect complex structure-function interactions. Evidence was found for neuroplasticity in dorsal higher visual areas, which may act to modulate acute visual dysfunction. Subsequent longitudinal analyses identified associations between early fMRI activation in the lateral occipital complexes, a ventral stream higher visual area, and longer term visual outcome, which were evident on stimulation of either eye, and independent of measures of myelination and neuroaxonal loss in the visual pathways. A quadrant-specific fMRI stimulation paradigm was used to investigate recovery from visual field defects, finding no evidence for field defect-specific neuroplastic responses. It was concluded that cortical neuroplasticity appears more important to recovery from ON than was previously thought, and its contribution is independent of measures of tissue damage. This may provide a target for future therapeutic approaches in demyelinating disease

MICROSTRUCTURE AND CONNECTIVITY OF THE CEREBELLUM WITH ADVANCED DIFFUSION MRI IN HEALTH AND PATHOLOGY

The cerebellum contains most of the central nervous system neurons and it is classically known to be a key region for sensorimotor coordination and learning. However, its role in higher cognitive functions has been increasingly recognised, thus raising the interest of neuroscience and neuroimaging communities. Despite this, knowledge of cerebellar structure and function is still incomplete and the interpretation of experimental results is often problematic. For these and also technical reasons the cerebellum is still frequently disregarded in magnetic resonance imaging (MRI) studies. Therefore, the principal aim of this work was to use MRI to investigate cerebellar microstructure and macrostructural connectivity in health and pathology, focusing also on technical aspects of image acquisition. The starting point of each project described in the present thesis were techniques, models and pipelines currently accepted in clinical practice. The meeting of inadequacies or problems of such techniques raised questions that pushed research to a more fundamental level. This thesis has three main contributions. The first part presents a clinical study of cerebellar involvement in processing speed deficits in multiple sclerosis, where combined tractography and network science highlighted the importance of the cerebellum in patients\u2019 cognitive performance. Then a deeper investigation conducted on high-quality diffusion MRI data with advanced diffusion signal models showed that subregions of the cerebellar cortex are characterised by different microstructural features: this represents one of the very first attempts to use diffusion MRI to face the widespread idea of cerebellar cortex uniformity, which has been recently challenged by findings from other research fields, thus providing new perspectives for the study of cerebellar information processing in health and pathology. Finally, the emerging technical problems that hamper the study of small structures within the cerebellum were tackled by developing dedicated acquisition protocols that exploit reduced field-of-view techniques for 3T and 7T MRI scanners

Functional Regeneration of Supraspinal Connections in a Patient With Transected Spinal Cord Following Transplantation of Bulbar Olfactory Ensheathing Cells With Peripheral Nerve Bridging

Treatment of patients sustaining a complete spinal cord injury remains an unsolved clinical problem because of the lack of spontaneous regeneration of injured central axons. A 38-year-old man sustained traumatic transection of the thoracic spinal cord at upper vertebral level Th9. At 21 months after injury, the patient presented symptoms of a clinically complete spinal cord injury (American Spinal Injury Association class A-ASIA A). One of the patient's olfactory bulbs was removed and used to derive a culture containing olfactory ensheathing cells and olfactory nerve fibroblasts. Following resection of the glial scar, the cultured cells were transplanted into the spinal cord stumps above and below the injury and the 8-mm gap bridged by four strips of autologous sural nerve. The patient underwent an intense pre- and postoperative neurorehabilitation program. No adverse effects were seen at 19 months postoperatively, and unexpectedly, the removal of the olfactory bulb did not lead to persistent unilateral anosmia. The patient improved from ASIA A to ASIA C. There was improved trunk stability, partial recovery of the voluntary movements of the lower extremities, and an increase of the muscle mass in the left thigh, as well as partial recovery of superficial and deep sensation. There was also some indication of improved visceral sensation and improved vascular autoregulation in the left lower limb. The pattern of recovery suggests functional regeneration of both efferent and afferent long-distance fibers. Imaging confirmed that the grafts had bridged the left side of the spinal cord, where the majority of the nerve grafts were implanted, and neurophysiological examinations confirmed the restitution of the integrity of the corticospinal tracts and the voluntary character of recorded muscle contractions. To our knowledge, this is the first clinical indication of the beneficial effects of transplanted autologous bulbar cells

The Effects of Daytime Melatonin Administration on Sleep, Higher Cognitive Function, and Changes in the Brain

This study investigated the effects of exogenous melatonin on people’s sleep, ability to perform an emotional Stroop task, and underlying brain architecture. 10 healthy adults (age = 26.8 ± 6.25 years) underwent a baseline period followed by an experimental period whereby melatonin was administered at inappropriate times, with daily activity logs kept throughout. The emotional Stroop task was performed four times during each period, followed by an MRI scan. Following melatonin administration, sleep and wake times were significantly shifted and sleep quality ratings were significantly decreased compared to baseline values. Additionally, processing of emotional words but not faces was negatively affected by the melatonin treatment. Fractional anisotropy and mean diffusivity values were also significantly altered in the inferior frontal gyrus. It is inferred that the melatonin treatment induced circadian desynchronization, resulting in behavioural changes and structural alterations in brain regions involved in performance of the emotional Stroop task