Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Après traitement d’un AIC par thrombolyse, les lésions ischémiques en diffusion peuvent être réversibles, stables et/ou progresser. Cette thèse a pour objectif d’étudier en IRM ces phénomènes de réversibilité et de progression, de mieux comprendre leur physiopathologie, et d’appréhender le rôle pronostic du volume des lésions en diffusion. La réversibilité en diffusion a été rapportée après recanalisation artérielle, chez l’animal et chez l’homme. Dans notre cohorte de 155 patients, nous avons étudié ce phénomène par une analyse voxel à voxel sur des IRM avant et 24h après thrombolyse. Nous avons montré que la réversibilité des anomalies en diffusion à 24h était fréquente et surtout persistait sur une IRM plus tardive (médiane 54h) pour plus de 70% des voxels [58.0-85.9], suggérant que ce phénomène n’était pas transitoire. De plus, seule la réversibilité permanente était associée à une amélioration neurologique à 24h (OR=1.15, CI95%[ 1.03-1.27], P=0.008 par mL). La substance blanche a été décrite comme plus résistante à l’ischémie sur des modèles murins. Chez l’homme, nous avons confirmé la prédominance en substance blanche des phénomènes de réversibilité, avec une probabilité de régression plus importante pour un voxel de substance blanche que pour un voxel de substance grise. Ces résultats pourraient aider à identifier avant décision thérapeutique les lésions potentiellement réversibles, c'est-à-dire celles prédominant en substance blanche. Même s’il existe une association entre le volume de lésion en diffusion avant traitement et le pronostic fonctionnel à 3 mois, la réversibilité des lésions pourrait remettre en cause les seuils de volume au-delà desquels une revascularisation pourrait être futile. En effet, en limitant la progression des anomalies en diffusion et en favorisant leur régression, la revascularisation pourrait aussi avoir un impact sur le pronostic fonctionnel des patients avec un large volume lésionnel (≥70mL). Dans une population de 267 patients avec un infarctus de l’artère cérébrale moyenne traités par thrombolyse, 54 avaient un volume en diffusion ≥70mL, dont 12(22%) avaient un pronostic fonctionnel favorable à 3 mois. L’odds-ratio de la recanalisation pour le pronostic fonctionnel favorable dans le groupe ≥70mL était de 4.87 [1.15-20.73], P=0.03 en faveur d’un impact positif de la recanalisation même dans ce groupe. En l’absence de reperfusion, les anomalies en diffusion progressent au sein de la pénombre ischémique. Selon le modèle « core/pénombre », cette progression lésionnelle ne doit pas s’accompagner d’une aggravation neurologique. Nous avons formulé l’hypothèse que si elle survenait au-delà de la pénombre (dans des zones asymptomatiques), elle s’accompagnerait d’une détérioration neurologique. La détérioration neurologique précoce non expliquée (absence de transformation hémorragique, d’œdème malin ou d’autre cause identifiable) est observée chez 7% de nos 309 patients thrombolysés. Nous avons validé l’hypothèse initiale d’une progression des anomalies en diffusion au-delà de la pénombre chez ces patients. Par une analyse voxel à voxel, elle était présente chez 9 cas/10 (7-137mL; > 10mL chez 8 cas), et son volume était significativement supérieur à celui des 30 contrôles sans détérioration précoce (P=0.047). De plus, sa topographie était congruente avec les fonctions neurologiques qui s’étaient détériorées. L’ensemble de ces résultats participe à une meilleure compréhension de l’évolution des lésions ischémiques aiguës en IRM de diffusion et offre des perspectives pour adapter la prise en charge individuelle afin d’améliorer le pronostic fonctionnel. / Within the first 24 hours after IV-rtPA, diffusion-weighted ischemic lesions can reverse, remain stable or grow. The aim of this thesis is to study these reversal and growth phenomena, to better understand their pathophysiology and to gain insight into the prognostic value of diffusion lesion volume. Diffusion lesion reversal was reported in animals and humans after arterial recanalization. In our sample of 155 patients, we studied this phenomenon with MRI performed before and 24 hours after thrombolysis using a voxel-based approach. First, we demonstrated that 24 hours diffusion reversal was frequent and sustained on a late MRI (median 54h) for over two-thirds of the voxels. Second, sustained reversal was associated with 24hr neurological improvement (OR=1.15, IC95%[ 1.03-1.27], P=0.008 per 1mL). Animal studies have suggested that white matter is more resistant to ischemia than gray matter. In humans, we confirmed that diffusion lesion reversal was more frequent in white matter than in gray matter and disclosed that white matter voxels were more prone to reverse than gray matter voxels. The amount of white matter in the initial diffusion lesion may therefore be a significant determinant of reversibility. Large diffusion lesion volume is associated with poor outcome. However, revascularization therapy can prevent infarct growth or even promote lesion reversal. It is still unclear whether these treatments are beneficial in patients with large diffusion volumes (≥70mL). In our series including 267 patients with middle cerebral artery stroke treated with thrombolysis, 54 patients had a ≥70mL diffusion volume, of which 12(22%) had a 3 month favorable outcome. Odds-ratio of recanalization for favorable outcome in the ≥70mL group was 4.87 [1.15-20.73], P=0.03 supporting a benefit of recanalization in this subgroup. Diffusion lesions growth is usually located within the ischemic penumbra. We hypothesized that if it occurred beyond its boundaries, it would translate into neurological deterioration. Unexplained early neurological deterioration is frequent (70% of early neurological deteriorations, 7% in our series of 309 thrombolysed patients) and its causes are not well-known (no symptomatic intra cerebral hemorrhage, malignant edema or post-stroke seizure). We confirmed our hypothesis in these patients with diffusion growth beyond the penumbra. This growth occurred in 9 of the 10 studied patients (7-137mL; > 10mL in 8 patients) and it was significantly larger than in the 30 controls with early neurological deterioration (P=0.047). Moreover its topography matched the neurological items that deteriorated. All together, these results contribute to a better understanding of acute ischemic lesions using diffusion-weighted imaging and may offer perspectives to adapt individual patient care.

Après traitement d’un AIC par thrombolyse, les lésions ischémiques en diffusion peuvent être réversibles, stables et/ou progresser. Cette thèse a pour objectif d’étudier en IRM ces phénomènes de réversibilité et de progression, de mieux comprendre leur physiopathologie, et d’appréhender le rôle pronostic du volume des lésions en diffusion. La réversibilité en diffusion a été rapportée après recanalisation artérielle, chez l’animal et chez l’homme. Dans notre cohorte de 155 patients, nous avons étudié ce phénomène par une analyse voxel à voxel sur des IRM avant et 24h après thrombolyse. Nous avons montré que la réversibilité des anomalies en diffusion à 24h était fréquente et surtout persistait sur une IRM plus tardive (médiane 54h) pour plus de 70% des voxels [58.0-85.9], suggérant que ce phénomène n’était pas transitoire. De plus, seule la réversibilité permanente était associée à une amélioration neurologique à 24h (OR=1.15, CI95%[ 1.03-1.27], P=0.008 par mL). La substance blanche a été décrite comme plus résistante à l’ischémie sur des modèles murins. Chez l’homme, nous avons confirmé la prédominance en substance blanche des phénomènes de réversibilité, avec une probabilité de régression plus importante pour un voxel de substance blanche que pour un voxel de substance grise. Ces résultats pourraient aider à identifier avant décision thérapeutique les lésions potentiellement réversibles, c'est-à-dire celles prédominant en substance blanche. Même s’il existe une association entre le volume de lésion en diffusion avant traitement et le pronostic fonctionnel à 3 mois, la réversibilité des lésions pourrait remettre en cause les seuils de volume au-delà desquels une revascularisation pourrait être futile. En effet, en limitant la progression des anomalies en diffusion et en favorisant leur régression, la revascularisation pourrait aussi avoir un impact sur le pronostic fonctionnel des patients avec un large volume lésionnel (≥70mL). Dans une population de 267 patients avec un infarctus de l’artère cérébrale moyenne traités par thrombolyse, 54 avaient un volume en diffusion ≥70mL, dont 12(22%) avaient un pronostic fonctionnel favorable à 3 mois. L’odds-ratio de la recanalisation pour le pronostic fonctionnel favorable dans le groupe ≥70mL était de 4.87 [1.15-20.73], P=0.03 en faveur d’un impact positif de la recanalisation même dans ce groupe. En l’absence de reperfusion, les anomalies en diffusion progressent au sein de la pénombre ischémique. Selon le modèle « core/pénombre », cette progression lésionnelle ne doit pas s’accompagner d’une aggravation neurologique. Nous avons formulé l’hypothèse que si elle survenait au-delà de la pénombre (dans des zones asymptomatiques), elle s’accompagnerait d’une détérioration neurologique. La détérioration neurologique précoce non expliquée (absence de transformation hémorragique, d’œdème malin ou d’autre cause identifiable) est observée chez 7% de nos 309 patients thrombolysés. Nous avons validé l’hypothèse initiale d’une progression des anomalies en diffusion au-delà de la pénombre chez ces patients. Par une analyse voxel à voxel, elle était présente chez 9 cas/10 (7-137mL; > 10mL chez 8 cas), et son volume était significativement supérieur à celui des 30 contrôles sans détérioration précoce (P=0.047). De plus, sa topographie était congruente avec les fonctions neurologiques qui s’étaient détériorées. L’ensemble de ces résultats participe à une meilleure compréhension de l’évolution des lésions ischémiques aiguës en IRM de diffusion et offre des perspectives pour adapter la prise en charge individuelle afin d’améliorer le pronostic fonctionnel. / Within the first 24 hours after IV-rtPA, diffusion-weighted ischemic lesions can reverse, remain stable or grow. The aim of this thesis is to study these reversal and growth phenomena, to better understand their pathophysiology and to gain insight into the prognostic value of diffusion lesion volume. Diffusion lesion reversal was reported in animals and humans after arterial recanalization. In our sample of 155 patients, we studied this phenomenon with MRI performed before and 24 hours after thrombolysis using a voxel-based approach. First, we demonstrated that 24 hours diffusion reversal was frequent and sustained on a late MRI (median 54h) for over two-thirds of the voxels. Second, sustained reversal was associated with 24hr neurological improvement (OR=1.15, IC95%[ 1.03-1.27], P=0.008 per 1mL). Animal studies have suggested that white matter is more resistant to ischemia than gray matter. In humans, we confirmed that diffusion lesion reversal was more frequent in white matter than in gray matter and disclosed that white matter voxels were more prone to reverse than gray matter voxels. The amount of white matter in the initial diffusion lesion may therefore be a significant determinant of reversibility. Large diffusion lesion volume is associated with poor outcome. However, revascularization therapy can prevent infarct growth or even promote lesion reversal. It is still unclear whether these treatments are beneficial in patients with large diffusion volumes (≥70mL). In our series including 267 patients with middle cerebral artery stroke treated with thrombolysis, 54 patients had a ≥70mL diffusion volume, of which 12(22%) had a 3 month favorable outcome. Odds-ratio of recanalization for favorable outcome in the ≥70mL group was 4.87 [1.15-20.73], P=0.03 supporting a benefit of recanalization in this subgroup. Diffusion lesions growth is usually located within the ischemic penumbra. We hypothesized that if it occurred beyond its boundaries, it would translate into neurological deterioration. Unexplained early neurological deterioration is frequent (70% of early neurological deteriorations, 7% in our series of 309 thrombolysed patients) and its causes are not well-known (no symptomatic intra cerebral hemorrhage, malignant edema or post-stroke seizure). We confirmed our hypothesis in these patients with diffusion growth beyond the penumbra. This growth occurred in 9 of the 10 studied patients (7-137mL; > 10mL in 8 patients) and it was significantly larger than in the 30 controls with early neurological deterioration (P=0.047). Moreover its topography matched the neurological items that deteriorated. All together, these results contribute to a better understanding of acute ischemic lesions using diffusion-weighted imaging and may offer perspectives to adapt individual patient care.

Fragestellung: Das von Dixon 1991 beschriebene tierexperimentelle Modell der 'controlled cortical impact injury'(CCII) wurde zur Untersuchung pathophysiologischer und pathomorphologischer Veränderungen nach traumatischer Hirnkontusion angewandt. Magnetresonanztomographische Techniken (MRT) einschließlich der diffusionswichtenden Bildgebung (DWI) wurden genutzt, um den Zeitverlauf der Hirnödementwicklung zu erfassen, eine Differenzierung unterschiedlicher Ödemformen zu ermöglichen und einen Blut-Hirn-Schrankenschaden zu detektieren. Desweiteren wurde die MRT genutzt, um den neuroprotektiven Effekt des NO-Synthase-Pathway-Modulators Lubeluzol, der bereits im Modell der zerebralen Ischämie nachgewiesen werden konnte, zu untersuchen. Material und Methoden: An 46 Sprague Dawley Ratten wurde eine links parieto-temporale Kontusion appliziert. Die Tiere wurden bis zu 7 Tage nach Trauma magnetresonanztomographisch untersucht. 36 Tiere erhielten Lubeluzol resp. Plazebo. Ergebnisse: Die T2-gewichtete Bildgebung zeigte eine maximale Ödemausbreitung 24 - 48 Stunden nach Trauma. Es ließ sich mithilfe der DWI ein Kontusionskern von einem Kontusionsrand differenzieren. Der Kontusionskern zeichnete sich bis 48 Stunden nach Trauma durch eine Abfall des apparenten Diffusionskoeffizienten (ADC) aus, einem zytotoxischem Ödem entsprechend, der Kontusionsrand wies während des gesamten Untersuchungszeitraums einen ADC-Anstieg auf, als Ausdruck eines vasogenen Ödems. Die T1-gewichtete Bildgebung konnte nach Kontrastmittel (KM)-Applikation durch die KM-Extravasation eine über 7 Tage anhaltende Störung der Blut-Hirnschranke detektieren. In der Lubeluzol-Studie ließ sich anhand der ADC-Veränderungen, des Ödemausmasses oder physiologischer Parameter wie Blutdruck, intrakranieller Druck oder Hirnschwellung kein signifikanter Unterschied zwischen den Tieren der Substanz- bzw. Plazebo-Gruppe aufzeigen. Schlußfolgerung: Die in dem Modell der CCII induzierte traumatische Hirnkontusion zeichnet sich bis 48 Stunden nach Trauma durch einen zytotoxischen Kontusionskern und einen diesen umgebenen vasogenen Kontusionrand aus. Desweiteren konnte ein anhaltender Blut-Hirnschrankendefekt nachgewiesen werden. Ein neuroprotektiver Effekt des Lubeluzols konnte in diesem Traumamodell in der hier applizierten Dosierung nicht nachgewiesen werden. / Objective: The controlled cortical impact injury (CCII) device, as described by Dixon 1991, was used to investigate the brain tissue damage in an animal model of severe traumatic brain injury. Magnetic resonance imaging (MRI) techniques including diffusion weighted imaging (DWI) have been applied to analyse the time course and the characteristics of edema formation and to detect blood-brain-barrier disruption. Furthermore MRI has been used to investigate a neuroprotective effect of the NO-synthase pathway modulator lubeluzole, which has proved markedly beneficial in a model of cerebral ischemia in rats. Material and Methods: a left parieto-temporal cortical contusion was inflicted upon 46 Sprague Dawley rats. Animals have been examined up to 7 days following trauma by MRI. 36 animals have been administered lubeluzole resp. placebo. Results: The most pronounced edema formation has been shown in T2-weighed imaging at 24 - 48 hours post trauma. DWI was able to distinguish between a contusion core and a contusion rim. The contusion core was marked by a decrease in the apparent diffusion coefficient (ADC) up to 48 hours post trauma, indicating cytotoxic edema, whereas the contusion rim has been characterised by vasogenic edema, as indicated by ADC-increase over the entire investigation period. In T1-weighted imaging contrast agent extravasation indicated a sustained blood brain barrier disruption up to 7 days after trauma. Compared to placebo administered rats in lubeluzole-treated animals no significant differences in ADC-changes, edema-extension or physiological parameters as blood pressure, intracranial pressure or brain swelling could be demonstrated. Conclusion: CCII induced traumatic brain injury is characterised by a cytotoxic edema up to 48 hours encircled by a vasogenic contusion rim accompanied by a sustained blood brain barrier disruption. In the model of CCII lubeluzole did not reveal a neuroprotective effect in the applied dosage.

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.

Our brain, perhaps the most sophisticated and mysterious part of the human body, to some extent, determines who we are. However, it’s a vulnerable organ. When subjected to an impact, such as a traffic accident or sport, it may lead to traumatic brain injury (TBI) which can have devastating effects for those who suffer the injury. Despite lots of efforts have been put into primary injury prevention, the number of TBIs is still on an unacceptable high level in a global perspective. Brain edema is a major neurological complication of moderate and severe TBI, which consists of an abnormal accumulation of fluid within the brain parenchyma. Clinically, local and minor edema may be treated conservatively only by observation, where the treatment of choice usually follows evidence-based practice. In the first study, the gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue. Thus, the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a Finite Element (FE) model. The model revealed that water content (WC) increment at the edema zone remained nearly identical for both supine and prone positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to axonal fibers of the central nervous system. These observations suggest that considering the patient’s head position during intensive care and at rehabilitation should be of importance to the treatment of edematous regions in TBI patients. In TBI patients with diffuse brain edema, for most severe cases with refractory intracranial hypertension, decompressive craniotomy (DC) is performed as an ultimate therapy. However, a complete consensus on its effectiveness has not been achieved due to the high levels of severe disability and persistent vegetative state found in the patients treated with DC. DC allows expansion of the swollen brain outside the skull, thereby having the potential in reducing the Intracranial Pressure (ICP). However, the treatment causes stretching of the axons and may contribute to the unfavorable outcome of the patients. The second study aimed at quantifying the stretching and WC in the brain tissue due to the neurosurgical intervention to provide more insight into the effects upon such a treatment. A nonlinear registration method was used to quantify the strain. Our analysis showed a substantial increase of the strain level in the brain tissue close to the treated side of DC compared to before the treatment. Also, the WC was related to specific gravity (SG), which in turn was related to the Hounsfield unit (HU) value in the Computerized Tomography (CT) images by a photoelectric correction according to the chemical composition of the brain tissue. The overall WC of brain tissue presented a significant increase after the treatment compared to the condition seen before the treatment. It is suggested that a quantitative model, which characterizes the stretching and WC of the brain tissue both before as well as after DC, may clarify some of the potential problems with such a treatment. Diffusion Weighted (DW) Imaging technology provides a noninvasive way to extract axonal fiber tracts in the brain. The aim of the third study, as an extension to the second study was to assess and quantify the axonal deformation (i.e. stretching and shearing)at both the pre- and post-craniotomy periods in order to provide more insight into the mechanical effects on the axonal fibers due to DC. Subarachnoid injection of artificial cerebrospinal fluid (CSF) into the CSF system is widely used in neurological practice to gain information on CSF dynamics. Mathematical models are important for a better understanding of the underlying mechanisms. Despite the critical importance of the parameters for accurate modeling, there is a substantial variation in the poroelastic constants used in the literature due to the difficulties in determining material properties of brain tissue. In the fourth study, we developed a Finite Element (FE) model including the whole brain-CSF-skull system to study the CSF dynamics during constant-rate infusion. We investigated the capacity of the current model to predict the steady state of the mean ICP. For transient analysis, rather than accurately fit the infusion curve to the experimental data, we placed more emphasis on studying the influences of each of the poroelastic parameters due to the aforementioned inconsistency in the poroelastic constants for brain tissue. It was found that the value of the specific storage term S_epsilon is the dominant factor that influences the infusion curve, and the drained Young’s modulus E was identified as the dominant parameter second to S_epsilon. Based on the simulated infusion curves from the FE model, Artificial Neural Network (ANN) was used to find an optimized parameter set that best fit the experimental curve. The infusion curves from both the FE simulations and using ANN confirmed the limitation of linear poroelasticity in modeling the transient constant-rate infusion. To summarize, the work done in this thesis is to introduce FE Modeling and imaging technologiesincluding CT, DW imaging, and image registration method as a complementarytechnique for clinical diagnosis and treatment of TBI patients. Hopefully, the result mayto some extent improve the understanding of these clinical problems and improve theirmedical treatments. / QC 20120201

Objectives: To compare 64-slice contrast-enhanced computed tomography (CT) with 3-Tesla magnetic resonance imaging (MRI) using Gd-EOB-DTPA for the diagnosis of hepatocellular carcinoma (HCC) and evaluate the utility of diffusion-weighted imaging (DWI) in this setting. Methods: 3-phase-liver-CT was performed in fifty patients (42 male, 8 female) with suspected or proven HCC. The patients were subjected to a 3-Tesla-MRI-examination with Gd-EOB-DTPA and diffusion weighted imaging (DWI) at b-values of 0, 50 and 400 s/mm2. The apparent diffusion coefficient (ADC)-value was determined for each lesion detected in DWI. The histopathological report after resection or biopsy of a lesion served as the gold standard, and a surrogate of follow-up or complementary imaging techniques in combination with clinical and paraclinical parameters was used in unresected lesions. Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values were evaluated for each technique. Results: MRI detected slightly more lesions that were considered suspicious for HCC per patient compared to CT (2.7 versus 2.3, respectively). ADC-measurements in HCC showed notably heterogeneous values with a median of 1.2±0.5×10−3 mm2/s (range from 0.07±0.1 to 3.0±0.1×10−3 mm2/s). MRI showed similar diagnostic accuracy, sensitivity, and positive and negative predictive values compared to CT (AUC 0.837, sensitivity 92%, PPV 80% and NPV 90% for MRI vs. AUC 0.798, sensitivity 85%, PPV 79% and NPV 82% for CT; not significant). Specificity was 75% for both techniques. Conclusions: Our study did not show a statistically significant difference in detection in detection of HCC between MRI and CT. Gd-EOB-DTPA-enhanced MRI tended to detect more lesions per patient compared to contrast-enhanced CT; therefore, we would recommend this modality as the first-choice imaging method for the detection of HCC and therapeutic decisions. However, contrast-enhanced CT was not inferior in our study, so that it can be a useful image modality for follow-up examinations.

Οι τεχνικές απεικόνισης μοριακής διάχυσης (DWI) και τανυστή διάχυσης (DTI) είναι από τις πιο δημοφιλείς τεχνικές μαγνητικής τομογραφίας (MRI) στην έρευνα του εγκεφάλου. Διάχυση (ή θερμική κίνηση Brown) είναι ένα τυχαίο φαινόμενο το οποίο περιγράφει τη μεταφορά υλικού (π.χ μόρια νερού) από μία χωρική θέση σε άλλη με την πάροδο του χρόνου. Η διάχυση του νερού σε βιολογικούς ιστούς παρατηρείται μέσα, έξω, γύρω από τις κυτταρικές δομές και είναι αποτέλεσμα της θερμικής ενέργειας των μορίων. Η κάθε τεχνική υποστηρίζεται από τον δικό της αλγόριθμο από τους οποίους προκύπτουν και οι αντίστοιχοι παραμετρικοί χάρτες. Πιο συγκεκριμένα από την τεχνική διάχυσης προκύπτει ο δείκτης της φαινόμενης σταθεράς διάχυσης (ADC-Apparent Diffusion Coefficient) , ενώ από την τεχνική του τανυστή διάχυσης προκύπτει ο δείκτης της κλασματικής ανισοτροπίας (FA-Fractional Anisotropy). Η παράμετρος ADC δείχνει πόσο διαφέρει η διάχυση στην περιοχή ενδιαφέροντος σε σχέση με την μέση τιμή διάχυσης. Η κλασματική ανισοτροπία (FA) είναι δείκτης μέτρησης του βαθμού ανισοτροπίας της διάχυσης και η τιμή της εξαρτάται άμεσα από την ακεραιότητα των νευρικών ινών. Το φάσμα εφαρμογής των δύο τεχνικών είναι ευρύ (εφαρμογή σε απομυελινωτικές νόσους, ισχαιμικά επεισόδια, εγκεφαλικοί όγκοι). Ο κύριος λόγος είναι ότι η διάχυση των μορίων νερού είναι ιδιαίτερα ευαίσθητη σε τυχόν αλλοιώσεις στη δομή των ινών της Λευκής ουσίας. Σκοπός της παρούσας ερευνητικής είναι η εφαρμογή των τεχνικών Τανυστή Διάχυσης (DTI) και Μοριακής Διάχυσης (DWI) σε τρείς κατηγορίες εγκεφαλικών όγκων (μηνιγγιώματα, γλοιώματα υψηλής και χαμηλής κακοήθειας, εγκεφαλικούς μεταστατικούς όγκους) με σκοπό τον διαχωρισμό αυτών. / The brain is a highly organized organ with a complex microstructural organization . The microstructural organization of brain tissue affects the molecular motion (diffusion) of water. Diffusion therefore reflects the structural organization of tissue. Diffusion imaging is a Magnetic Resonance (MR) imaging technique that allows the quantification to the molecular motion of water. Magnitude and directionality (anisotropy) of molecular motion of water can be described. Measurements of the magnitude of diffusion have been used to identify abnormal tissue in tumors, stroke, multiple sclerosis and status epilepticus. Diffusion tensor imaging (DTI) is a relatively new technique that allows rotationally invariant measurements of both magnitude and directionality of water diffusion. DTI sequences with calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) scalars allow characterization of the shape and magnitude of the diffusion ellipsoid. These parameters consequently reflect the microstructural architecture of the human brain. In addition, quantification of diffusion can be especially helpful as it may allow early diagnosis of pathology . The purpose of this study was to correlate the changes in FA and ADC between three different brain tumors and outline the probability of presurgical tumor differentiation.

Après traitement d’un AIC par thrombolyse, les lésions ischémiques en diffusion peuvent être réversibles, stables et/ou progresser. Cette thèse a pour objectif d’étudier en IRM ces phénomènes de réversibilité et de progression, de mieux comprendre leur physiopathologie, et d’appréhender le rôle pronostic du volume des lésions en diffusion. La réversibilité en diffusion a été rapportée après recanalisation artérielle, chez l’animal et chez l’homme. Dans notre cohorte de 155 patients, nous avons étudié ce phénomène par une analyse voxel à voxel sur des IRM avant et 24h après thrombolyse. Nous avons montré que la réversibilité des anomalies en diffusion à 24h était fréquente et surtout persistait sur une IRM plus tardive (médiane 54h) pour plus de 70% des voxels [58.0-85.9], suggérant que ce phénomène n’était pas transitoire. De plus, seule la réversibilité permanente était associée à une amélioration neurologique à 24h (OR=1.15, CI95%[ 1.03-1.27], P=0.008 par mL). La substance blanche a été décrite comme plus résistante à l’ischémie sur des modèles murins. Chez l’homme, nous avons confirmé la prédominance en substance blanche des phénomènes de réversibilité, avec une probabilité de régression plus importante pour un voxel de substance blanche que pour un voxel de substance grise. Ces résultats pourraient aider à identifier avant décision thérapeutique les lésions potentiellement réversibles, c'est-à-dire celles prédominant en substance blanche. Même s’il existe une association entre le volume de lésion en diffusion avant traitement et le pronostic fonctionnel à 3 mois, la réversibilité des lésions pourrait remettre en cause les seuils de volume au-delà desquels une revascularisation pourrait être futile. En effet, en limitant la progression des anomalies en diffusion et en favorisant leur régression, la revascularisation pourrait aussi avoir un impact sur le pronostic fonctionnel des patients avec un large volume lésionnel (≥70mL). Dans une population de 267 patients avec un infarctus de l’artère cérébrale moyenne traités par thrombolyse, 54 avaient un volume en diffusion ≥70mL, dont 12(22%) avaient un pronostic fonctionnel favorable à 3 mois. L’odds-ratio de la recanalisation pour le pronostic fonctionnel favorable dans le groupe ≥70mL était de 4.87 [1.15-20.73], P=0.03 en faveur d’un impact positif de la recanalisation même dans ce groupe. En l’absence de reperfusion, les anomalies en diffusion progressent au sein de la pénombre ischémique. Selon le modèle « core/pénombre », cette progression lésionnelle ne doit pas s’accompagner d’une aggravation neurologique. Nous avons formulé l’hypothèse que si elle survenait au-delà de la pénombre (dans des zones asymptomatiques), elle s’accompagnerait d’une détérioration neurologique. La détérioration neurologique précoce non expliquée (absence de transformation hémorragique, d’œdème malin ou d’autre cause identifiable) est observée chez 7% de nos 309 patients thrombolysés. Nous avons validé l’hypothèse initiale d’une progression des anomalies en diffusion au-delà de la pénombre chez ces patients. Par une analyse voxel à voxel, elle était présente chez 9 cas/10 (7-137mL; > 10mL chez 8 cas), et son volume était significativement supérieur à celui des 30 contrôles sans détérioration précoce (P=0.047). De plus, sa topographie était congruente avec les fonctions neurologiques qui s’étaient détériorées. L’ensemble de ces résultats participe à une meilleure compréhension de l’évolution des lésions ischémiques aiguës en IRM de diffusion et offre des perspectives pour adapter la prise en charge individuelle afin d’améliorer le pronostic fonctionnel. / Within the first 24 hours after IV-rtPA, diffusion-weighted ischemic lesions can reverse, remain stable or grow. The aim of this thesis is to study these reversal and growth phenomena, to better understand their pathophysiology and to gain insight into the prognostic value of diffusion lesion volume. Diffusion lesion reversal was reported in animals and humans after arterial recanalization. In our sample of 155 patients, we studied this phenomenon with MRI performed before and 24 hours after thrombolysis using a voxel-based approach. First, we demonstrated that 24 hours diffusion reversal was frequent and sustained on a late MRI (median 54h) for over two-thirds of the voxels. Second, sustained reversal was associated with 24hr neurological improvement (OR=1.15, IC95%[ 1.03-1.27], P=0.008 per 1mL). Animal studies have suggested that white matter is more resistant to ischemia than gray matter. In humans, we confirmed that diffusion lesion reversal was more frequent in white matter than in gray matter and disclosed that white matter voxels were more prone to reverse than gray matter voxels. The amount of white matter in the initial diffusion lesion may therefore be a significant determinant of reversibility. Large diffusion lesion volume is associated with poor outcome. However, revascularization therapy can prevent infarct growth or even promote lesion reversal. It is still unclear whether these treatments are beneficial in patients with large diffusion volumes (≥70mL). In our series including 267 patients with middle cerebral artery stroke treated with thrombolysis, 54 patients had a ≥70mL diffusion volume, of which 12(22%) had a 3 month favorable outcome. Odds-ratio of recanalization for favorable outcome in the ≥70mL group was 4.87 [1.15-20.73], P=0.03 supporting a benefit of recanalization in this subgroup. Diffusion lesions growth is usually located within the ischemic penumbra. We hypothesized that if it occurred beyond its boundaries, it would translate into neurological deterioration. Unexplained early neurological deterioration is frequent (70% of early neurological deteriorations, 7% in our series of 309 thrombolysed patients) and its causes are not well-known (no symptomatic intra cerebral hemorrhage, malignant edema or post-stroke seizure). We confirmed our hypothesis in these patients with diffusion growth beyond the penumbra. This growth occurred in 9 of the 10 studied patients (7-137mL; > 10mL in 8 patients) and it was significantly larger than in the 30 controls with early neurological deterioration (P=0.047). Moreover its topography matched the neurological items that deteriorated. All together, these results contribute to a better understanding of acute ischemic lesions using diffusion-weighted imaging and may offer perspectives to adapt individual patient care.

The primate visual system is organised and wired in a topological manner. From the eye well into extrastriate visual cortex, a preserved spatial representation of the vi- sual world is maintained across many levels of processing. Diffusion-weighted imaging (DWI), together with probabilistic tractography, is a non-invasive technique for map- ping connectivity within the brain. In this thesis I probed the sensitivity and accuracy of DWI and probabilistic tractography by quantifying its capacity to detect topolog- ical connectivity in the post mortem macaque brain, between the lateral geniculate nucleus (LGN) and primary visual cortex (V1). The results were validated against electrophysiological and histological data from previous studies. Using the methodol- ogy developed in this thesis, it was possible to segment the LGN reliably into distinct subregions based on its structural connectivity to different parts of the visual field represented in V1. Quantitative differences in connectivity from magno- and parvo- cellular subcomponents of the LGN to different parts of V1 could be replicated with this method in post mortem brains. The topological corticocortical connectivity be- tween extrastriate visual area V5/MT and V1 could also be mapped in the post mortem macaque. In vivo DWI scans previously obtained from the same brains have lower resolution and signal-to-noise because of the shorter scan times. Nevertheless, in many cases, these yielded topological maps similar to the post mortem maps. These results indicate that the preserved topology of connection between LGN to V1, and V5/MT to V1, can be revealed using non-invasive measures of diffusion-weighted imaging and tractography in vivo. In a preliminary investigation using Human Connectome data obtained in vivo, I was not able to segment the retinotopic map in LGN based on con- nections to V1. This may be because information about the topological connectivity is not carried in the much lower resolution human diffusion data, or because of other methodological limitations. I also investigated the mechanisms of perceptual learning by developing a novel task-irrelevant perceptual learning paradigm designed to adapt neuronal elements early on in visual processing in a certain region of the visual field. There is evidence, although not clear-cut, to suggest that the paradigm elicits task- irrelevant perceptual learning, but that these effects only emerge when practice-related effects are accounted for. When orientation and location specific effects on perceptual performance are examined, the largest improvement occurs at the trained location, however, there is also significant improvement at one other 'untrained' location, and there is also a significant improvement in performance for a control group that did not receive any training at any location. The work highlights inherent difficulties in inves- tigating perceptual learning, which relate to the fact that learning likely takes place at both lower and higher levels of processing, however, the paradigm provides a good starting point for comprehensively investigating the complex mechanisms underlying perceptual learning.