It is essential to characterize and quantify naturally occurring morphometric changes in the human brain when investigating the onset or progression of neurodegenerative disorders. The aim of this thesis is to characterize the properties and measure the performance of several popular automated magnetic resonance image analysis tools dedicated to brain morphometry. The thesis begins with an overview of morphometric analysis methods, followed by a literature review focusing on cortical parcellation protocols. Our work identified unanimous protocol weaknesses across all packages in particular issues when addressing cortical variability. The next chapters present a ground truth dataset and a dedicated software to analyse manually parcellated data. The dataset (https://datashare.is.ed.ac.uk/handle/10283/2936) includes 10 healthy middle-aged subjects, whose metrics we used as reference against automated tools. To develop the ground truth dataset, we also present a manual parcellation protocol (https://datashare.is.ed.ac.uk/handle/10283/3148) providing step-by-step instructions for outlining three cortical gyri known to vary with ageing and dementia: the superior frontal gyrus, the cingulate gyrus and the supramarginal gyrus. The software, Masks2Metrics (https://datashare.is.ed.ac.uk/handle/10283/3018), was built in Matlab to calculate cortical thickness, white matter surface area, and grey matter volume from 3D binary masks. Characterizing these metrics allowed further understanding of the assumptions made by software when creating and measuring anatomical parcels. Next, we present results from processing the raw T1-weighted volumes in the latest versions of several automated image analysis tools-FreeSurfer (versions 5.1 and 6.0), BrainGyrusMapping, and BrainSuite (version 13a)- against our ground truth. Tool repeatability for the same system was confirmed as multiple runs yielded identical results. Compared to our ground truth, the closest results were generated by BrainGyrusMapping for volume metrics and by FreeSurfer 6.0 for thickness and surface area metrics. In conclusion, our work sheds light on the significance of clearly detailed parcellation protocols and accurate morphometric tools due to the implications that they both will have. We therefore recommend extra caution when selecting image analysis tools for a study, and the use of independent publicly available ground truth datasets and metrics tools to assist with the selection process.

In den letzten Jahren ist zunehmend deutlich geworden, dass die Multiple Sklerose (MS) nicht nur eine Erkrankung der weißen Substanz des zentralen Nervensystems ist, sondern auch häufig und beträchtlich die graue Substanz in allen klinischen Verlaufsformen betrifft. Besonders die kortikale Pathologie mit entmarkten Läsionen wurde durch verbesserte immunhistochemische Färbetechniken und neuen magnetresonanztomographischen Verfahren ausführlicher untersucht. MS-Patienten leiden klinisch oft an körperlichen Beeinträchtigungen und neuropsychologischen Defiziten, welche die Lebensqualität beeinflussen. Diese Symptome wurden mit Läsionen in der grauen Substanz assoziiert. Mechanismen, die zu dieser Pathologie führen, müssen daher aufgeklärt werden um vorbeugende oder akute Behandlungen entwickeln zu können. Zur pathologischen Untersuchung der grauen Substanz werden angemessene Tiermodelle benötigt, welche die humane kortikale Pathologie wiederspiegeln. Das am häufigsten verwendete Tiermodell in MS-Studien ist die Experimentelle Autoimmune Enzephalomyelitis (EAE), die in ihrem ‘konventionellen’ Immunisierungsprotokoll nur selten den zerebralen Kortex betrifft. Ein EAE-Modell mit Einbezug des Kortex, das MS-Läsionen nachahmt, wurde in Ratten beschrieben. Hierzu wurden proinflammatorische Zytokine in eine vorbestimmte kortikale Region injiziert. Da spezifisch genveränderte Rattenstämme fehlen um die Mechanismen der Pathologie in der grauen Substanz zu untersuchen ist es notwendig das Tiermodell in Mäusen zu entwickelen. Das Ziel dieses Projekts war die Entwicklung eines kortikalen EAE-Mausmodells sowie dessen histopathologische Charakterisierung. Desweiteren wurde kortikales Gehirnmaterial von MS-Patienten im späten Krankheitsstadium auf dendritische Patholgie untersucht. Die kortikale EAE wurde in Myelin Oligodendrozyten Glykoprotein (MOG)-immunisierten BiozziABH (hohe Antikörper) und F1 Nachkommen, die aus BiozziABH und Mäusen mit einem C57BL6/J-Hintergrund generiert worden sind, durch die intrakortikale Injektion von TNF-α und IFN-γ induziert. Histologische Untersuchungen zeigten eine ausgedehnte subpiale Entmarkung und Entzündung im Kortex drei Tage nach der Zytokininjektion in der betroffenen Hirnhälfte. Die Entzündung ging innerhalb von drei Wochen fast vollständig zurück und entmarkte Regionen wiesen teilweise eine Remyelinisierung auf. Axone blieben in läsionalen Regionen erhalten und neuronaler Verlust wurde im Kortex nicht beobachtet. Desweiteren wurde eine Methode etabliert, die es erlaubt detailliert dendritische Pathologien in der Maus zu untersuchen. Kortex-enthaltenes Autopsiematerial von progressiven MS-Patienten mit langandauerndem Krankheitsverlauf zeigte einen Verlust von dendritischen Dornfortsätzen (Spines) in Neurone, die in den unteren korikalen Layern sowohl in chronisch entmarkten Läsionen als auch im umliegenden normal erscheinendem Gewebe der grauen Substanz lokalisiert waren. Im vorliegenden Projekt wurde ein kortikales EAE-Mausmodell entwickelt, das die humane MS-Pathologie der grauen Substanz in frühen Krankheitsstadien wiederspiegelt. Dieses Modell ist für Untersuchungen früher Mechanismen im entmarkten Kortex und für die Erprobung therapeutischer Behandlungen wie die Erhöhung der Remyelinisierung nützlich. Darüberhinaus wurde ein ausgedehnter Verlust dendritischer Dornfortsätze im zerebralen Kortex in chronischen MS-Patienten gezeigt, der auf oft beobachtete neuropsychologische Defizite zurückgeführt werden könnte.

Recently, Magnetic Resonance Imaging (MRI) has found great traction in monitoring the effects of Caloric Restriction (CR) on the brain, specifically gray matter. However, there are no streamlined, simple pipelines in existence to analyze data generated from these kinds of MRI studies. Therefore, my hypothesis is two-fold: the first part being the development of a dynamic and straightforward image processing pipeline, which I have tailored to fit the unique needs of the CR data involved in this study. This data brings me to the second part of my hypothesis, which is to use that pipeline to highlight the decreased attenuation in grey matter induced by long-term CR. In order to test the second portion of my hypothesis, T1/MPRAGE scans were collected from 17 male Rhesus Macaques, half of which were maintained on a 30% reduced calorie diet for an average of 22 years, starting around age 3. Using this basis, the inherent properties of the MR images were exploited by the novel pipeline, and used to analyze whether or not CR reduces the attenuation of grey matter atrophy, with regards to aging

The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.

<p>The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.</p>

No description available.

Study objective - The aim was to determine whether areas in the periaqueductal grey matter, medial dorsal raphé, or ventrolateral medulla might be involved with the integration of blood pressure and heart rate during isometric exercise.Design - Cats were anaesthetised with α chloralose (75 mg·kg-1) and catheters inserted into the right jugular vein and carotid artery. Isometric contractions were generated using a microprocessor controlled stimulator and sleeve electrode around the tibial nerve. Bilateral lesions were made in the dorsal periaqueductal grey matter (P1.0, LR 2.0, HD + 1.5 mm) or two sites in the ventrolateral medulla (P12.0, RL 2.0, HD -10 mm; or P12.0, RL 2.0, HD -8.5 mm). Lesions were also made in the medial dorsal raphé nuclei (P1.0, RL 0.0, HD +1.5 mm). Clonidine was injected into the cerebral aqueduct to determine whether it would exert an antipressor effect during muscle contraction after the lesions were made. Only one site of lesion was made in a group of animals. Bilateral injections of clonidine (250 ng in 0.5 μl) were made into the intact ventrolateral medulla (P11.5, RL 4.0, HD -8.5 mm) to explore its role further. Fatiguing contractions were performed before and after the lesions were made, or clonidine was injected, and changes in arterial blood pressure and heart rate were measured. Verification of the lesion sites or the microinjection sites, and the extent of the lesion or spread of the clonidine, was made from histological examination of brain tissue after each experiment.Experimental material - Adult cats of either sex, n = 20, weight 2.4 (SD 0.4) kg, were used.Measurements and main results - Fatiguing isometric contractions in control conditions caused mean arterial pressure to increase by 45-50 mm Hg and heart rates by 20-25 beats·min-1. Bilateral lesions in the dorsal periaqueductal grey matter did not alter resting mean arterial pressure but attenuated the pressor response during contractions. Injections of clonidine into the cerebral aqueduct had no further antipressor effects after the lesions. Lesions of the medial dorsal raphé nuclei or injections of clonidine into the intact medial dorsal raphé nuclei did not affect the pressor response to fatiguing isometric contractions. Injections of clonidine into the intact ventrolateral medulla eliminated the pressor response to isometric contractions. Bilateral lesions of the ventrolateral medulla near the rostral lateral border of the inferior olivary tract nuclei (P12.0, LR 2.0, HD -10 mm) also attenuated the muscle pressor response, while subsequent injections of clonidine into the cerebral aqueduct depressed the changes in blood pressure further.Conclusions - Ergoreceptor information may be processed through the periaqueductal grey matter through the ventrolateral medulla to control arterial blood pressure during isometric exercise to fatigue.

Le but de ce travail est d’étudier deux dimensions sémiologiques, identifiées dans la littérature comme associées au trouble dépressif résistant, l’anxiété et l’apathie. Ces marqueurs cliniques et leurs corrélats radiologiques seront ensuite testés dans une analyse longitudinale du pronostic à 6 mois d’une cohorte de patients souffrant de dépression. Les données originales de ce travail sont issues de la cohorte LONGIDEP. Cette étude prospective, naturalistique, a été menée chez des patients souffrant d’un épisode dépressif majeur qui bénéficiaient, dans le cadre des soins courants, d’une évaluation clinique, neuropsychologique et d’une imagerie cérébrale à l’inclusion. Une nouvelle évaluation a été proposée à 6 mois de l’inclusion. Cette étude nous a permis de montrer que 1) l’apathie dans la dépression est associée à un profil clinique et physiopathologique spécifique, 2) l’analyse catégorielle et sémiologique de l’anxiété dans une population de sujet déprimés résistants n’étaient pas concordantes. Les déprimés résistants présentaient une hyperperfusion amygdale centro-médiane, 3) l’anxiété trait, un pattern cognitif associé à la mémoire visuo-spatiale étaient prédictifs d’une évolution péjorative de la dépression. Des anomalies structurales de régions impliquées dans la régulation émotionnelle et plus précisément l’adaptation au danger/peur, étaient associées à une évolution péjorative de la dépression. Des deux dimensions sémiologiques étudiées, l’anxiété apparaît être impliquées dans le pronostic de la dépression. L’étude des liens entre l’anxiété et les troubles de la motivation est une perspective de recherche pour la dépression résistante. / The aim of this work is to study anxiety and apathy in treatment resistant depression. These clinical factors and its imaging correlates will be tested in prediction of outcome in a 6-months follow-up. Original data were retrieved in LONGIDEP cohort. This is a prospective study conducted in routine care. Patients suffering from a mood depressive episode benefited from a clinical, neuropsychological and brain imaging. They were assessed once again at 6 months. Our study has shown that 1) apathy in depression is associated with specific clinical and pathophysiological patterns, 2) categorical and dimensional approach of anxiety in treatment resistant depression are not convergent. This latter population exhibited higher brain perfusion of centro-medial amygdala, 3) trait anxiety, cognitive patterns of visuospatial memory were predictive of pejorative outcome. Structural abnormalities in key regions involved in emotion regulation were associated with pejorative outcome of depression. Only anxiety was involved in outcome of depression. The link between anxiety and motivation should be studied in further works.

No description available.

While evidence suggests there is indeed a relationship between arterial stiffness and changes in brain structure and function cross-sectionally, the longitudinal relationship between arterial stiffness and changes in brain structure and function is unclear. Also unclear is whether a regional effect of arterial stiffness on brain structure exists, or if the effect is homogenous across brain regions. Using a healthy cohort of the UK Biobank study (N = 1858, meanSD: 61  7 years), we investigated the longitudinal association between changes in arterial stiffness index (ASI) and brain structure (grey matter cortical thickness, whole brain grey matter volume, white matter hyperintensity volume) and function (cognitive performance in 6 tests) over 2.5  1 years. We also examined the association between baseline ASI and all structural and functional brain outcomes 8-11 years post-baseline (N = 630). Prior to post-hoc correction, we observed a significant effect of changes in ASI over 2.5  1 years on grey matter cortical thickness in 11 brain regions contributing to reductions between 0.0004-0.0024mm annually, but none of the 11 regions remained significant post-correction. Following correction there was also no effect of changes in ASI on whole brain grey matter volume (p = 0.76), white matter hyperintensity volume (p = 0.84), or cognitive performance in the domains of interest. Baseline ASI was not associated with regional grey matter cortical thickness, white matter hyperintensity volume, or cognitive function, but did have a significant negative association with whole brain grey matter volume 8.5  1.05 (p = 0.015) years later and 11  1.02 (p = 0.03) years later. Our findings suggest that taken with the effect of age, elevations in ASI may have an additive effect to accelerate changes in brain structure beyond the range that is to be expected as a part of normal aging. Our findings also suggest the relationship between ASI and reductions in whole brain grey matter volume may require long-term exposure to elevations in arterial stiffness in otherwise healthy older adults. / Thesis / Master of Science in Kinesiology / Arterial stiffening both accompanies the normal aging process and can progress due to acquired health conditions. As arteries begin to stiffen the ability to buffer high pressure blood flow is impaired and can put microvasculature at risk of damage. Microvascular damage in the brain can disrupt blood and subsequent oxygen delivery to the brain. When delivery to the brain does not meet the metabolic demand, changes in brain structure brain can occur. Changes in brain structure are associated with impaired brain function, as well as potentially accelerating the progression of neurological diseases. What remains unclear is whether arterial stiffness impacts brain structure differently across regions or all regions homogenously. The purpose of this thesis was to examine the relationship between arterial stiffness and structural and functional changes in the brain over time (objective 1: 2-5 years; objective 2: 8-11 years). Our observations suggest that the progression of arterial stiffness had an effect that was equivalent to approximately 30% of the rate of grey matter tissue loss associated with normal healthy aging (~0.25% reduction in grey matter per year). We found no effect of changes in arterial stiffness on the progression of total grey matter volume, white matter lesions or brain function. We did observe a significant negative relationship between arterial stiffness at baseline and total grey matter volume 8-11 years later. We found no relationship between baseline arterial stiffness and brain structure or function 8–11-years post-baseline. Taken with the effects of normal aging, the loss of tissue in select brain regions associated with changes in arterial stiffness may result in grey matter reductions beyond the range associated with what is considered healthy or normal aging. The association of arterial stiffness and total grey matter volume 8-11 years later suggests that changes in whole brain structure are the product of long-term exposure to arterial stiffness.