Traumatic brain injury (TBI) continues to be a widespread problem in the United States with approximately 1.7 million occurrences annually [1]. Current automotive crash test standards use the Head Injury Criterion (HIC) [2] to assess head injury potential, but this metric does not relate an impact to underlying damage. For an injury metric to effectively predict TBI, it is crucial to relate level of impact to resulting injury. The research presented in this dissertation explains the development and repeatability of two novel injury devices, impact response characterization over the course of 24 hours in the Gottingen minipig and the relationships between metabolite changes, underlying disruption, and impact kinematics, and the characterization of impact response over the course of 72 hours. The translation-input and combined translation and rotation-input injury devices were shown to be repeatable, minimizing the number of animals needed for testing. Impact response over the course of 24 hours showed axonal disruption through immunostaining and proton magnetic resonance spectroscopy. The translation-input injury group metabolite analyses revealed the initial stages of glutamate excitotoxicity while the combined-input injury group showed a clear pathway for glutamate excitotoxicity. Numerous correlative relationships and potential underlying disruption predictors were found between metabolites, immunostaining, and kinematics. The most promising predictor combination for the translation-input injury device was N-acetylaspartylglutamate/Scyllo at 24 hours compared to 1 hour and linear speed for predicting underlying light neurofilament disruption. For the combined-input injury device, the strongest predictor combination was Glutamine/N-acetylaspartylglutamate at 24 hours compared to baseline and angular acceleration for predicting underlying light neurofilament disruption. Statistically significant predictors were found between Glutamate+Glutamine/Total Creatine at 24 hours compared to baseline and all kinematics and injury metrics with an angular component for predicting heavy neurofilament disruption. Analyses over the course of 72 hours revealed persistent axonal disruption and metabolite perturbations. Overall, this dissertation and the complementary parts of this project have many societal implications. Due to the high incidence of traumatic brain injury, there is a need for prevention, mitigation, and treatment strategies. Developing a new injury metric will help improve prevention strategies, especially in the automotive, sporting, and military environments. 1 Faul, M., Xu, L., Wald, M. M., and Coronado, V. G. (2010). Traumatic Brain Injury in the United States. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2 Versace, J. (1971). A Review of the Severity Index. SAE Technical Paper. No. 710881 / Ph. D.

<p>Rolandic epilepsy (RE) is the most common focal epilepsy syndrome in the pediatric age group with an onset between 3 and 13 years. The syndrome is defined by electro-clinically typical features and has been considered benign according to seizure remission before the age of 16 years.</p><p>The aim of this thesis was to investigate children with typical RE with different methods and to discuss the delineation of the syndrome. Thirty-eight children, aged 6–14 years, participated in one up to four studies.</p><p>Eighteen children were investigated with MRI. Hippocampal abnormalities were found in six (33%), volume asymmetry in five (28%) and high signal intensities on T2-weighted images in three (17%). Additionally, high signal intensities in T2-weighted images were revealed subcortically in temporal and frontal lobes bilaterally in five children (28%).</p><p>The hippocampal region was evaluated metabolically using proton magnetic resonance spectroscopy (¹H-MRS) in 13 children with RE and 15 matched controls. A metabolic asymmetry of the hippocampal regions was found in the patients compared to controls indicating an abnormal neuronal function.</p><p>Seventeen children with RE and 17 matched controls were investigated with a neuropsychological test battery. The RE children showed lower performance in auditory-verbal tests and in executive functions compared to controls.</p><p>Twenty RE children and 24 controls were assessed concerning their oromotor function. The RE children had greater problems concerning tongue movements including articulation. A dichotic listening test was also performed in a subgroup showing poorer results in the RE group. </p><p>A simple classification is proposed with RE ‘pure’ as the main group and the frame for this study.</p><p>In conclusion, these investigations disclosed various abnormalities in children with RE, challenging the benign concept during the active phase. It is assumed that maturational factors comprise causal mechanism to the deviant findings, which probably successively will normalize.</p>

Rolandic epilepsy (RE) is the most common focal epilepsy syndrome in the pediatric age group with an onset between 3 and 13 years. The syndrome is defined by electro-clinically typical features and has been considered benign according to seizure remission before the age of 16 years. The aim of this thesis was to investigate children with typical RE with different methods and to discuss the delineation of the syndrome. Thirty-eight children, aged 6–14 years, participated in one up to four studies. Eighteen children were investigated with MRI. Hippocampal abnormalities were found in six (33%), volume asymmetry in five (28%) and high signal intensities on T2-weighted images in three (17%). Additionally, high signal intensities in T2-weighted images were revealed subcortically in temporal and frontal lobes bilaterally in five children (28%). The hippocampal region was evaluated metabolically using proton magnetic resonance spectroscopy (1H-MRS) in 13 children with RE and 15 matched controls. A metabolic asymmetry of the hippocampal regions was found in the patients compared to controls indicating an abnormal neuronal function. Seventeen children with RE and 17 matched controls were investigated with a neuropsychological test battery. The RE children showed lower performance in auditory-verbal tests and in executive functions compared to controls. Twenty RE children and 24 controls were assessed concerning their oromotor function. The RE children had greater problems concerning tongue movements including articulation. A dichotic listening test was also performed in a subgroup showing poorer results in the RE group. A simple classification is proposed with RE ‘pure’ as the main group and the frame for this study. In conclusion, these investigations disclosed various abnormalities in children with RE, challenging the benign concept during the active phase. It is assumed that maturational factors comprise causal mechanism to the deviant findings, which probably successively will normalize.

The objectives of our study were to determine the potential of 1H MRS in detecting (1) early colonic inflammation, (2) effects of various fatty acids on normal colon and (3) their effects on IBD. Sprague dawley rat fed with 2% carrageenan was used as a model of IBD. Flaxseed oil served as ω-3, corn oil as ω-6 and beef tallow as saturated fatty acid sources. Control group animals were fed 5% corn oil, whereas, those in high-fat diet groups received an additional 7% of the respective fatty acids. After 2 weeks, 1H MRS and histology were conducted on excised colonic mucosa. Statistical classification strategy (SCS) used for analyzing 1H MRS data achieved an accuracy of 82 % in stage 1, 90-100% in stage 2 and 96-100% in stage 3. This implies that 1H MRS is a sensitive tool to diagnose early IBD and the effects of dietary fat on IBD.

The objectives of our study were to determine the potential of 1H MRS in detecting (1) early colonic inflammation, (2) effects of various fatty acids on normal colon and (3) their effects on IBD. Sprague dawley rat fed with 2% carrageenan was used as a model of IBD. Flaxseed oil served as ω-3, corn oil as ω-6 and beef tallow as saturated fatty acid sources. Control group animals were fed 5% corn oil, whereas, those in high-fat diet groups received an additional 7% of the respective fatty acids. After 2 weeks, 1H MRS and histology were conducted on excised colonic mucosa. Statistical classification strategy (SCS) used for analyzing 1H MRS data achieved an accuracy of 82 % in stage 1, 90-100% in stage 2 and 96-100% in stage 3. This implies that 1H MRS is a sensitive tool to diagnose early IBD and the effects of dietary fat on IBD.

La composition en acides gras du tissu adipeux mammaire est reconnue comme marqueur qualitatif de la consommation lipidique antérieure mais aussi de la part nutritionnelle du risque / pronostic du cancer du sein. Ceci ouvre la perspective d’individualiser dans la population générale, un groupe de personnes à risque, susceptibles de bénéficier d’une intervention nutritionnelle ciblée. L’approche du dépistage d’une population à risque par l’utilisation de la composition du tissu adipeux comme biomarqueur se heurte i) à l’aspect invasif que représente le prélèvement d’un fragment de tissu adipeux mammaire, et ii) à la lourdeur contraignante du conditionnement et de l’analyse systématique des acides gras du tissu adipeux. Les méthodes analytiques actuellement disponibles sont incompatibles avec la perspective d’un dépistage de masse. Cependant, les descriptions récentes de l’utilisation de la spectroscopie par résonance magnétique (SRM) pour décrire la composition lipidique des triglycérides du tissu adipeux permettent d’envisager de l’utiliser dans cet objectif. Ce travail de thèse présente: 1) l’évaluation de la SRM pour caractériser la composition en acides gras du tissu adipeux chez l’animal (le rat) suite à une intervention nutritionnelle, 2) l’évaluation du profil lipidique du tissu adipeux par SRM chez la femme sur une plateforme clinique 3T, 3) l’étude des liens entre la composition en acides gras du tissu adipeux et la présentation du cancer du sein, et 4) la comparaison des données de la SRM in vitro (11.7T) et in vivo (3T) du tissu adipeux chez des patientes prises en charge pour un cancer du sein avec les données de la chromatographie gazeuse. / Fatty acid composition of the white adipose tissue remains the most reliable qualitative biomarker of previous dietary intake of fatty acids and may provide information on the nutritional part of the risk or evolution of breast cancer. This opens the prospect of individualization of women at high nutritional risk of breast cancer that may benefit from a targeted nutritional intervention but 1) the need for biopsy and 2) subsequent time-consuming biochemical analyses hamper any application of this approach. Proton magnetic resonance spectroscopy (1H-MRS) of adipose tissue lipids represents an appealing, non-invasive approach, which could circumvent these limitations. This manuscript reports: 1) an assessment of feasibility of (1H-MRS) to evaluate the consequences of a nutritional intervention in a rat mammary tumor model on the adipose tissue fatty acid composition, 2) an assessment of the feasibility of in vivo measurement of the fatty acid composition of breast adipose tissue by (1H-MRS) on a clinical platform, 3) an assessment of the relation of specific patterns of composition of adipose tissue fatty acids with the presentation of breast cancer, and 4) a comparison with gas chromatography of (1H-MRS) data acquired on breast adipose tissue in vitro (11.7T) and in vivo (3T) on patients managed for breast cancer.

Introduction: Bone loss, fractures, and declining physical performance are associated with muscle atrophy and fat infiltration. Muscle structure and composition differences may be apparent between women with and without osteoporosis (OP). Purpose: To: 1) evaluate the effect of a time period spent in supine on magnetic resonance imaging (MRI) measures of muscle size and diffusion properties in young and older women; 2) assess the feasibility of applying three MRI scanning methods to evaluate macrostructural and microstructural properties of leg muscles in older women; and 3) compare musculoskeletal tissue structure and composition between older women with and without OP, and to determine the relationships between bone, muscle, fat, and physical performance. Methods: Sixteen young and older women had their legs scanned with MRI at baseline and after 30 and 60 minutes of supine resting. Feasibility of recruitment, participant tolerance to scanning, and image acquisition and analysis protocols were assessed. Thirty-five moderately active, older women with and without OP underwent MRI and peripheral quantitative computed tomography scanning of the leg and performed physical performance tests. Results: In young and older women, muscle size did not change with time spent supine, but water diffusivity decreased in some muscle regions. It is feasible to perform a single session of three MRI scanning techniques in older women. Women with and without OP had similar musculoskeletal structure that showed fat infiltration is associated with reduced bone strength and slower gait speed. Conclusions: In young and older women, muscle size is unaffected by a period of supine rest, but time spent in supine may modify water diffusivity measures. It is feasible to use a combination of MRI scanning techniques to evaluate leg muscle structure in older women. MRI improves our understanding of the relationships among muscle, fat, bone, and physical performance. / Dissertation / Doctor of Science (PhD)

Bildgebende Studien haben gezeigt, dass bei schizophrenen Patienten Positivsymptome mit Veränderungen mesolimbischer Aktivierungsmuster unter Einbeziehung des Nucleus accumbens in Zusammenhang stehen. Hierbei ist von besonderem Interesse, dass der Nucleus accumbens Teil des Belohnungssystems ist, wobei die integrale „Bewertung“ belohnungsanzeigender Reize präfrontalen kortikalen Strukturen, insbesondere dem anterioren Zingulum, zuzurechnen ist. Bereits in der Antizipationsphase potentiell belohnender Reize, werden vermutlich zur Berechnung von Prädiktionsabweichungen dopaminerge Signale in der VTA generiert und modulieren den Nucleus accumbens. Es gibt zahlreiche Hinweise, dass glutamaterge Neurone des anterioren Zingulums die Dopaminausschüttung im Nucleus accumbens beeinflussen, und dass diese Modulation bei Erkrankungen wie der Schizophrenie beeinträchtigt ist. Ziel der vorliegenden Arbeit war es, mittels funktioneller Magnetresonanztomographie und Protonen Magnetresonanzspektroskopie, Hinweise über den Zusammenhang zwischen der glutamatergen Neurotransmission des ACC und belohnungsassoziierter Dopaminausschüttung im Nucleus accumbens bei 23 gesunden Probanden und bei 23 unmedizierten schizophrenen Patienten zu erlangen. Die Ergebnisse weisen darauf hin, dass die gegenseitige Modulation von anteriorem Zingulum und Nucleus accumbens bei schizophrenen Patienten gestört ist. Dieses und weitere Ergebnisse wurden im theoretischen Rahmen der NMDA-Rezeptor-Hypoaktivität und einer gestörten Balance zwischen Dopamin-D1- und Dopamin-D2-Rezeptor-Aktivität als pathophysiologische Korrelate schizophrener Erkrankungen diskutiert. / Imaging studies have demonstrated that for schizophrenic patients a correlation exists between positive symptoms and changes in the patterns of mesolimbic activity. Especially the changes in the ncl. accumbens (Nac) were interpreted in connection with the reward system. The signals indicating reward are thought to be processed by the anterior cingulum (ACC). These structures attribute meaning to the reward signals. In the anticipation phase of a potentially rewarding stimulus, dopaminergic signals from the VTA are generated in prediction of expected or aberrant outcome, thus modulating the Nac. Data indicate a direct modulation of the Nac. by glutamatergic neurons of the anterior cingulum. A major aim of this thesis is to establish a connection between the reward associated dopaminergic signals of the ncl. accumbens and the glutamatergic projections of the acc in unmedicated schizophrenic patients and healthy controls. The methods included measurements of proton magnetic resonance spectroscopy (1H-MRS) and functional MRI-scans done at a 3-Tesla tomograph. The paradigm applied was a modified version of the monetary incentive delay paradigm (Knutson et al. 2000). In healthy volunteers we found a significant negative correlation between the glutamate concentration in the ACC and the BOLD-contrast in the Nac (reward versus neutral), in contrast to the findings in schizophrenic patients. A significant higher BOLD-contrast was seen in the anticipation phase in healthy controls. The results were incorporated in a model of NMDA-R-Hypoaktivity. In addition to discussing the functional aspects for the structures involved the model was further expanded to include the hypothesis of a disturbed balance between dopamine-D1- and -D2-receptor activity and a dysfunctional hippocampal gating-process. The so constructed model suggests a profound striato-thalamo-cortical filter disturbance as the basis of the observed aberrations in the reward processing in schizophrenic disorders.

The neurophysiological basis of cognition changes with age is relatively unexplained, with most studies reporting weak relationships between cognition and measures of brain function, such as event related potentials, brain size and cerebral blood flow. Proton magnetic resonance spectroscopy (1H-MRS) is an in vivo method used to detect metabolites within the brain that are relevant to certain brain processes. Recent studies have shown that these metabolites, in particular N-acetyl aspartate (NAA), which is associated with neuronal viability, correlate with performance on neuropsychological tests or other measures of cognitive function in patients with a variety of cognitive disorders associated with ageing and in normal ageing subjects. We have studied the relationship between metabolites and cognitive function in elderly patients 3 months and 3 years after a stroke or transient ischemic attack (TIA) and in an ageing comparison group. Metabolites were no different between stroke/TIA patients and elderly controls, however, there were significant metabolite differences between stroke/TIA patients with cognitive impairment (Vascular Cognitive Impairment and Vascular Dementia) and those without. Frontal measures of NAA and NAA/Cr predicted cognitive decline over 12 months and 3 years in stroke/TIA patients and elderly controls, and these measures were superior predictors than structural MRI measures. Longitudinal stability of metabolites in ageing over 3 years was associated with stability of cognitive function. The results indicate that 1H-MRS is a useful tool in differentiating stroke/TIA patients with and without cognitive impairment, with possibly superior predictive ability than structural MRI for assessing future cognitive decline. The changes in 1H-MRS that occur with ageing and cognitive decline have implications for the neurophysiological mechanisms and processes that are occurring in the brain, as well as application to clinical diagnosis, the early detection of pathology and the examination of longitudinal change.

Ziele: Mittels absolutquantifizierender Protonen-Magnet-Resonanz-Spektroskopie (1H-MRS) wollten wir das Ergebnis einer Vorstudie bestätigen, die im Frontallappen einen reduzierten Quotienten von myo-Inositol/Gesamtcreatin (mI/tCr) bei Depressiven fand. Darüber hinaus testeten wir den antidepressiven Effekt von Inositol als Add-on-Therapie. Methodik: Wir untersuchten Einzelvoxel (2 x 2 x 2 cm3) in der weißen Substanz der rechten und linken Präfrontalregion mit Hilfe eines 3-Tesla Bruker Medspec Systems (STEAM Sequenz, TR/TE/TM = 6000/20/30 ms). Die einzelnen Metabolite wurden anhand des cerebralen Wassers als internem Standard quantifiziert (nach dem LCModell). Es wurden 24 unmedizierte Patienten mit unipolaren depressiven Episoden mit 24 alters- und geschlechtsgematchten gesunden Kontrollen verglichen. In doppelblindem, Plazebo-kontrollierten Parallelgruppen-Design erhielten die Patienten täglich 18 Gramm Inositol oder Plazebo zusätzlich zu Citalopram über vier Wochen. Ergebnisse: An der Baseline unterschieden sich die mI-, Cholin- und N-Acetyl-Aspartat-Konzentrationen der Patienten nicht von jenen der Kontrollen. Es fanden sich keine sich keine signifikanten Unterschiede zwischen Inositol- und Plazebo-Gruppe. Überraschenderweise zeigten die depressiven Patienten an der Baseline gegenüber den Kontrollen signifikant höhere tCr-Konzentrationen (mmol/kg) links (5,57 ± 0,96 vs. 4,87 ± 0,63; + 15 %, p < 0,01) und rechts präfrontal (5,29 ± 0,92 vs. 4,46 ± 0,41; + 17 %, p < 0,01). Nach der Behandlung ergab sich eine Reduktion der tCr-Konzentration links- (Tag 28: 5,05 ± 1,16; – 12 %, p = 0,08) und rechtsfrontal (Tag 28: 4,61 ± 1,07; – 9 %, p = 0,09). Die tCr-Konzentrationen der Patienten am Tag 28 unterschieden sich nicht mehr von jenen der Kontrollen. Zusammenfassung: Wir zeigten eine reversible Steigerung der tCr-Konzentration der Patienten im Vergleich zu Kontrollen, die auf Veränderungen des Creatin-Transports oder der ATP-Synthese bei unmedizierter unipolarer Depression hinweisen könnte. / Objectives: By means of proton magnetic resonance spectroscopy (1H-MRS) with absolute quantification we wanted to confirm our previous finding of decreased ratios of the metabolites myo-Inositol/total creatine (mI/tCr) in the right frontal brain of depressives. Moreover, we tested the antidepressive effect of oral Inositol ingestion as add-on-therapy. We measured concentrations (mmol/kg ww) of mI, tCr (= Creatine + Phosphocreatine), Choline (Cho) and N-Acetyl-Aspartate (NAA) in the frontal brain. Methods: Single voxels (2x2x2 cm3) in the white matter of the left and right prefrontal region were examined in a three Tesla Bruker Medspec System (STEAM sequence, TR/TE/TM = 6000/20/30 ms). Metabolites were quantified using the LCModel. At baseline, 24 drug-free patients with unipolar depressive episodes were compared to 24 age and sex matched healthy controls. In a double blind, placebo controlled parallel-group design patients received daily 18 grams Inositol or placebo as an add on therapy to Citalopram over four weeks. Results: At baseline, mI, Cho and NAA concentrations showed no significant differences between patients and controls. The treatment with Inositol did not result in any significant differences to the treatment with placebo. Surprisingly the patients showed significant higher tCr concentrations in the left (5.57 ± 0.96 vs. 4.87 ± 0.63; + 15 %, p < 0.01) as well as in the right prefrontal region (5.29 ± 0.92 vs. 4.46 ± 0.41; + 17 %, p < 0.01) compared to controls. The treatment caused a trend towards a decrease of tCr in the left (day 28: 5.05 ± 1.16; – 12 %, p = 0.08) and in the right frontal hemisphere (day 28: 4.61 ± 1.07; – 9 %, p = 0.09) compared to baseline. The differences between the patients’ tCr at day 28 and the tCr of controls were no more significant. Conclusion: We have found a state dependent increase of tCr concentration indicating bifrontal deviations in Creatine transport or ATP synthesis in drug free unipolar depressives.