<p>Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes.</p><p>Early changes in cerebral blood flow (CBF) and metabolism (CMRO₂) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO₂ was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.</p>

<p>This thesis demonstrates that infants represent temporarily non-visible, or occluded, objects. From 4 months of age, infants could accurately predict the reappearance of a moving object after 660 ms of non visibility; indicating accurate spatiotemporal representations. At this age predictions were dominated by associations between specific events and outcomes (associative rules). Between 6 and 8 months of age predictions became dominated by extrapolations (Study III). From 6 months infants could represent occluded objects for up to 4 seconds. The number of successful predictions decreased, however, if the information contained in the occlusion event diminished (time of accretion and deletion). As infants grew older (up to 12 months) they produced more accurate predictions. (Study II). The similarities between adult and infant performances were numerous (Study I). These conclusion are based on one cross sectional (Study I) and two longitudinal studies (Study II & III) in which an object, a ‘happy face’, moved on circular (Study I, II, & III) and other complex trajectories (Study III). One portion of each trajectory was covered by a screen that blocked the object from sight. In each study participants gaze were recorded with an infrared eye tracking system (ASL 504) and a magnetic head tracker (Flock of Birds). This data was combined with data from the stimulus and stored for of line analysis.</p>

Augmented Reality (AR) is an emerging technology that utilizes computer vision methods to overlay virtual objects onto the real world scene so as to make them appear to co-exist with the real objects. Its main objective is to enhance the user’s interaction with the real world by providing the right information needed to perform a certain task. Applications of this technology in manufacturing include maintenance, assembly and telerobotics. In this paper, we explore the potential of teaching a robot to perform an arc welding task in an AR environment. We present the motivation, features of a system using the popular ARToolkit package, and a discussion on the issues and implications of our research. / Singapore-MIT Alliance (SMA)

Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes. Early changes in cerebral blood flow (CBF) and metabolism (CMRO2) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO2 was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.

This thesis demonstrates that infants represent temporarily non-visible, or occluded, objects. From 4 months of age, infants could accurately predict the reappearance of a moving object after 660 ms of non visibility; indicating accurate spatiotemporal representations. At this age predictions were dominated by associations between specific events and outcomes (associative rules). Between 6 and 8 months of age predictions became dominated by extrapolations (Study III). From 6 months infants could represent occluded objects for up to 4 seconds. The number of successful predictions decreased, however, if the information contained in the occlusion event diminished (time of accretion and deletion). As infants grew older (up to 12 months) they produced more accurate predictions. (Study II). The similarities between adult and infant performances were numerous (Study I). These conclusion are based on one cross sectional (Study I) and two longitudinal studies (Study II &amp; III) in which an object, a ‘happy face’, moved on circular (Study I, II, &amp; III) and other complex trajectories (Study III). One portion of each trajectory was covered by a screen that blocked the object from sight. In each study participants gaze were recorded with an infrared eye tracking system (ASL 504) and a magnetic head tracker (Flock of Birds). This data was combined with data from the stimulus and stored for of line analysis.

Sex steroids in general and estrogens in particular – in addition to their effects on the reproductive organs – affect a large number of crucial bodily functions, including “higher” brain functions. Neuropeptides constitute the phylogenetically oldest neurotransmitter system and are currently thought to act mainly during stress, disease or injury. The concentration of galanin is i.a. up-regulated by injury to the nervous system and by estrogen. The main focus of the present thesis was to investigate whether the reported neuroprotective effect of 17β-estradiol in experimental animal stroke models is partially mediated through its effects on galanin and if galanin per se exerts neuroprotective effects in stroke. An exploratory study of the effects of sex steroid concentrations due to gender and pubertal development showed differences in concentrations of i.a. the neuropeptides galanin and neuropeptide Y also in brain regions of female rats important for higher brain functions, including hippocampus and cortex, brain regions not directly involved in reproduction. Puberty brings about changes in several hormonal mechanisms, and our studies showed that the major effect on the concentrations of galanin in various brain regions of ovariectomized (ovx) rats, was brought about by 17β-estradiol. The pathophysiological mechanisms involved in thrombolysis – the current treatment of choice in human stroke – attempts the re-establishment of perfusion (reperfusion) to the lesioned area of the brain. This prompted us to develop a reperfusion stroke model in rats designed to be mild, focal and transient, allowing long-term observation periods of animals thriving well postoperatively. Mortality and morbidity during and after the middle cerebral artery (MCA) occlusion are important confounding factors crucial for the results. Changing anaesthesia from intraperitoneally administered chloral hydrate to isofl urane inhalation anaesthesia using endotracheal intubation and controlled ventilation markedly reduced the mortality rate from 25% to 10.6%, which was even further reduced down to 2.7 % by successively improved surgical skills. Contrary to our initial hypothesis, long-term 17β-estradiol treatment resulted in larger ischemic lesions in our stroke model compared to control treatment. After 3 days the cerebral ischemic lesion area was doubled after 17β-estradiol treatment in rats subjected to 60 min microclip occlusion of the MCA followed by reperfusion. A similar, but not statistically signifi cant difference was found after 7 and 14 days. Three groups studying different types of experimental animal stroke and different doses of 17β-estradiol treatment have recently also demonstrated lack of neuroprotection by 17β-estradiol treatment. Furthermore, large epidemiological clinical studies have recently also reported an increased risk and poorer outcome in postmenopausal women subjected to hormone replacement therapy. The concentrations of galanin-like immunoreactivity in extracts of punch biopsies from the penumbra area after transient MCA occlusion were found unchanged, but were decreased (p=0.015) in the apparently undamaged ipsilateral hippocampus. Galanin administered by continuous intracerebroventricular infusion (2.4 nmol/day) resulted in a 30% larger ischemic lesion compared to controls, measured 7 days after the MCA occlusion. Taken together, these results indicate that galanin in the brain is primarily a factor reacting to ischemic injury rather than a neuroprotective factor in its own right. Very limited information is available about the steady state serum concentrations of 17β-estradiol in response to different modes of administration to rats for days and weeks. The need for this information has become especially apparent during recent years due to the observable dichotomy of estrogens effects – neuroprotective or not – in the various animal models of brain ischemia reported in the current scientific literature. The cause of this dichotomy is likely to be found in the experimental setup, including the mode of administration of 17β-estradiol. Delayed steady state of serum 17β-estradiol concentrations were found when comparing two common modes of exogenous administration of 17β-estradiol – slow-release osmotic pumps vs. daily subcutaneously injections of 17β-estradiol solved in sesame oil – to ovx rats during 2 times 6 weeks crossover treatment. Steady state was reached at week 4 in the daily injections group compared to at week 6 in the slow release osmotic pumps group. Once steady state was reached, the concentration was the same in both groups for the reminder of the experiment (in total 12 weeks). / On the day of the public defence of the doctoral thesis, the status of article V was: Available on line since 24th of May 2005.

Background Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains. Methods We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability. Results The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method. Conclusions The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality. / <p>Funding Agencies|County Council of Ostergotland, Sweden||</p>

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Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.

Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.