Human social interaction crucially depends on the ability to attribute thoughts and beliefs to other individuals. This ability is referred to as Theory of Mind (ToM), and understanding that other people can have false beliefs about the world is considered to be a critical test of ToM. In childhood, a developmental breakthrough is achieved around the age of 4 years, when children start explicitly reasoning about others’ false beliefs. The cognitive and neural developments that lead to this milestone of human cognition, however, are currently unknown. Moreover, recently, novel im- plicit paradigms have shown that, already before the age of 2 years, infants display correct expectations of the actions of an agent with a false belief. The processes that underlie these expectations and their relation to the later-developing explicit false belief reasoning, however, are unclear. The current thesis addresses these open issues in three studies. The first study investigates the developmental trajectory and robustness of an implicit false belief task longitudinally from the age of 2 to 4 years. We find that children only perform above chance by the age of 4 years, but not at 2 and 3 years. This indicates that early success on implicit false belief tasks is fragile. The second study examines the correlation of implicit and explicit false belief tasks with each other and with co-developing cognitive abilities. This shows a dissociation of implicit and explicit false belief tasks in that performance on the two task types does not correlate, and that explicit false belief tasks correlate with syntactic and executive functions, whereas implicit false be- lief tasks do not. Finally, the third study shows that the maturation of white matter in brain regions that support false belief reasoning in adultsand of their dorsal connectivity to the inferior frontal gyrus, suggested to support hierarchical processing, is associated with the emergence of explicit false belief reasoning in 3- and 4-year-old children. These associations are independent of implicit false belief-related action anticipation and of developments in other cognitive domains. Taken together, our results speak for a dissociation of the processes underlying implicit and explicit false belief tasks. We suggest that the developmental breakthrough in explicit false belief reasoning around the age of 4 years might result from improved belief processing, emerging hierarchical processing abilities, and the maturation of the connection between the relevant brain regions. Furthermore, I speculate on processes that might underlie early success on implicit false belief tasks in infancy.:Acknowledgements iii Summary xi Deutsche Zusammenfassung xvii 1 General Introduction 1.1 Theory of Mind . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1.1 Precursors of ToM in Infancy . . . . . . . . . . . . . 3 1.1.2 False Belief Understanding . . . . . . . . . . . . . . . 4 1.1.3 Relation between Implicit and Explicit False Belief Tasks . . . . . . . 8 1.1.4 Theoretical Accounts of the Emergence of ToM . . . 14 1.2 Relation to Other Cognitive Domains . . . . . . . . . . . . . 20 1.2.1 Executive Function . . . . . . . . . . . . . . . . . . . 25 1.2.2 Language . . . . . . . . . . . . . . . . . . . . . . . . 26 1.2.3 Correlations with Implicit False Belief Tasks . . . . . 29 1.3 Neural Basis of ToM . . . . . . . . . . . . . . . . . . . . . . 31 1.3.1 Neural Basis of ToM in Adults . . . . . . . . . . . . . 31 1.3.2 Neural Basis of ToM in Development . . . . . . . . . 35 1.3.3 Structural Brain Development in Early Childhood . . 36 1.4 Research Questions and Hypotheses . . . . . . . . . . . . . . 38 2 Study 1: Longitudinal evidence for 4-year-olds’ but not 2- and 3-year-olds’ false belief-related action anticipation . . . . . . . . . . . .45 3 Study 2: Implicit and explicit false belief development in preschool children . . . . . . . . . . . .73 4 Study 3: White matter maturation is associated with the emergence of Theory of Mind in early childhood . . . . . . . . . . . .91 5 General Discussion 5.1 Is there a continuity from early-developing to later explicit false belief abilities? . . . . . . . . . . . . . . . . . . . . . . . 106 5.2 What is the relation of implicit and explicit false belief tasks to other cognitive domains? . . . . . . . . . . . . . . . . . . 109 5.3 What is the neural basis of the emergence of ToM? And what does this tell us about the underlying cognitive processes? . . . . 114 5.4 What processes underlie implicit false belief tasks?. . . . . 118 5.5 Future Research and Limitations . . . . . . . . . . . . . . . 120 5.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 References . . . . . . . 128 A Supplements Study 1 . . . . . . . 161 B Supplements Study 2 . . . . . . . 163 C Supplements Study 3 . . . . . . . .181 Abbreviations . . . . . . . . 187 List of Figures . . . . . . . . 191 List of Tables . . . . . . . . 193

Obesity has been associated with accelerated cognitive decline during ageing and an increased risk for dementia (Fergenbaum et al., 2009; Fitzpatrick et al., 2009; Gustafson et al., 2009; Whitmer et al., 2008). However, recent discussions are questioning this detrimental relationship (Prickett et al., 2015). A protective effect of midlife obesity was found in a large epidemiologic study (Qizilbash et al., 2015), whereas a meta-analysis showed that midlife obesity increases the risk of dementia (Albanese et al., 2017). Methodological difference and reverse causation could be the reasons for such conflicting results (Gustafson, 2015; Kivimäki et al., 2018). For example, some studies used either body mass index (BMI) or waist-to-hip ratio (WHR); their results suggested abdominal or central obesity, which is measured by WHR or waist circumference, is more detrimental for cognitive decline than global obesity measured by BMI (Gustafson et al., 2009; Whitmer et al., 2008). Therefore, in order to assess the effect of body fat on cognitive function in a large group of community-dwelling healthy adults, we used both BMI and WHR as indicators for adiposity (Study 1). To better understand cognitive changes, it is important to investigate obesity-related brain changes. Regarding to brain structure, high body fat has been associated with decreased total brain volume and regional grey and white matter volume (Willette and Kapogiannis, 2015). However, the findings regarding white matter volume are inconsistent; obesity was found to be associated with decreased as well as increased white matter volumes (Bobb et al., 2014; Driscoll et al., 2012; Karlsson et al., 2013; Walther et al., 2010). Because of the inconsistency, diffusion-weighted imaging (DWI), which assesses the microstructural architecture, has been considered to have higher agreements among studies on obesity and decreased directional property of white matter (Willette and Kapogiannis, 2015). However, a recent study reported a positive association between obesity and white matter microstructure (Birdsill et al., 2017). The conflicting results may be explained by the relative small–medium sample size (n = 15– 268) among the studies and limited statistical power for data-driven whole brain voxel- wise analyses. Following the thought of increasing statistical power with bigger samples might be beneficial and more reliable, we investigated the link between body fat and white matter microstructure using a population-based sample of 1255 participants in Study 1. The obesity-related changes in the brain is considered to be a result of neuroinflammation. The neuroinflammation is likely caused by high fat intake- and excess adipose tissue-induced peripheral inflammation, which in turn leads to insulin resistance and hyperglycaemia; and these all together could also affect the hippocampus and result in memory inhibition (O’Brien et al., 2017; Pugazhenthi et al., 2016). A number of studies reported a negative association between obesity and hippocampal volume (Debette et al., 2011; Raji et al., 2010; Taki et al., 2008). However, others found a positive association (Widya et al., 2011) or no association (Bobb et al., 2014; Debette et al., 2011; Driscoll et al., 2012). This could be due to the fact that hippocampus comprises several subfields (cornu ammonis fields [CA1–4], the dentate gyrus [DG], and the subiculum), and these subfields have distinct functional properties (Deng et al., 2010; Strien et al., 2009; Yassa and Stark, 2011). It has also been reported that the hippocampal subfields are affected by ageing differently (Malykhin et al., 2017). Because the hippocampus is highly susceptible to degenerative processes (Pfefferbaum et al., 2013; Raz et al., 2010) and possesses neurogenesis ability in adults (Eriksson et al., 1998), it is often a key target in intervention studies. Several studies indicate that lifestyle interventions can be effective to combat obesity and to restore cognitive functions (Siervo et al., 2011). A double-blind randomised controlled trial of 1260 older individuals (aged 60–77 years) from the FINGER study showed that the intervention group obtained higher scores in a neuropsychological test battery compared to the control group after a 2-year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring) (Ngandu et al., 2015). Dietary nutrients that have anti-inflammatory or anti-oxidative effects, such as omega-3 fatty acids and polyphenols, have been associated with improved cognitive function and brain structural changes (Gómez-Pinilla, 2008; Huhn et al., 2015). Resveratrol is one type of polyphenols and occurs in variety of plants such as red grapes and blueberries (Baur et al., 2006). It has been reported to be associated with glucose metabolism and insulin sensitivity (Liu et al., 2014) as well as improved cognitive functions (Huhn et al., 2015; Marx et al., 2018). However, some studies reported no improvements in cognition after intervention (Köbe et al., 2017; Wightman et al., 2015). Besides the possibility that resveratrol does not affect cognition, another reason for these results could be that resveratrol is only effective in healthy ageing population (Evans et al., 2017; Witte et al., 2014) but not in young (Wightman et al., 2015) or patient population (Köbe et al., 2017). Therefore, replication studies with healthy older adults could help to evaluate whether there is an effect of resveratrol on cognitive function. Following this idea, we have conducted a double-blind randomised controlled trial (Study 2) with comprehensive neuropsychological test battery to assess the effect of resveratrol using 60 elderly subjects. In Study 1, we applied whole brain voxel-wise analysis to explore the correlations between overall obesity (measured by BMI) or abdominal obesity (WHR) and white matter microstructure. We found a negative correlation between BMI as well as WHR and fractional anisotropy (FA), a measure of microstructural architecture, in multiple white matter tracts independent of confounding factors. We further explored the indirect link of obesity and cognitive dysfunction using mediation analysis. In the mediation analysis, an indirect path through obesity-associated clusters was considered. We found that although obesity had no direct effect on executive functions and processing speed, it affected cognitive performance through lower FA in callosal and associative fibre tracts. We found the correlation between obesity and memory performance was not mediated by FA in the selected white matter tracts. In Study 2, we conducted a randomised trial for the effect of resveratrol on memory performance and hippocampal structure. We found that intake of resveratrol did not show any beneficial effect on either glucose metabolism or cognitive performance. Neither volume nor mean diffusivity (MD), another measure of microstructural architecture, showed changes after the intervention compared to the placebo group. However, subtle ageing- or lifestyle-related changes in the MD of the hippocampus were detected. This demonstrated that MD outperforms volumetric measures for detecting subtle changes of the hippocampus. The reason we could not observe any changes after resveratrol intake might be that this compound does not have an effect or that other lifestyle changes undermined the effect of resveratrol as neuroplasticity can be influenced by many factors. This thesis highlights that body fat is associated with lower FA in the white matter of the brain. This may indicate some widespread damage to the white matter; and mediation analysis indicates abdominal obesity is linked to poorer executive functions and processing speed through lower FA. Further this thesis shows that adding a dietary supplementation of resveratrol for six months does not improve memory or hippocampal structure in the present cohort of healthy adults with a large BMI range. Future studies should investigate longitudinal changes of body fat and brain structure in order to establish the causal relationship among obesity, white matter microstructure, and cognitive function. And more comprehensive lifestyle interventions combining diet, exercise, and cognitive training should be considered instead of one single approach to prevent and hopefully preserve obesity induced changes in cognition and in the brain.

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<div>Since the discovery of chronic traumatic encephalopathy (CTE) in retired professional football players, the long-term neurological safety of these athletes has been called into</div><div>question. Studies revealed that those who play football are at higher risk for developing neurological deficits such as Parkinson’s and Alzheimer’s diseases. It has also been observed that participation in contact sports can result in neurological changes detectable with magnetic resonance imaging (MRI) that do not present with any easily observable clinical symptoms. Changes in brain chemistry, structure, and blood flow have been observed over the course of a season of contact sports. These changes are thought to be caused by the repetitive head acceleration events (HAEs) sustained by contact sport athletes, with the magnitude and number of HAEs correlating with some changes. This dissertation aims to characterize and reduce the HAEs sustained by contact sport athletes with a specific focus on football players.</div><div><br></div><div>Studies of middle school and high school football players revealed that there are likely offsetting effects that result in similar HAEs between the two groups. As one plays at higher levels of play with typically bigger, stronger, faster athletes that should result in higher magnitude HAEs, there is likely an improvement in tackling technique used at higher levels that make it so there are similar HAEs among different levels of play. Examining middle school football and high school football and girls’ soccer athletes indicate that players that play on two teams (i.e. a player that plays both Varsity and Junior Varsity) may be at an increased risk for neurological changes due to over-exposure. It was revealed when studying post-collegiate football the up stance offensive linemen may help reduce the frequency of HAEs compared to the down stance. However, the skill of the offensive lineman needs to be accounted for to determine if it is beneficial for players to start in this stance.</div><div><br></div><div>Repetitive HAEs (rHAEs), whether due to body or direct head impacts arising from participation in contact sports, are correlated with alterations in white matter health. Fractional anisotropy (FA) and mean diffusivity (MD), two metrics used to assess white matter structural integrity, typically change in opposite directions (one increases while the other decreases) after brain injury. This study investigated the manner in which participation in American football affects the percentage of white matter exhibiting the four possible change combinations: increased FA, increased MD; decreased FA, increased MD; increased FA, decreased MD; decreased FA, decreased MD. Diffusion tensor imaging data of 61 high school football and 15 non-contact athletes were analyzed. After a season of participation, football athletes exhibited a significantly greater percentage of deviant voxels in each of the four categories than were observed from test-retest of non-contact athletes. Even prior to a season of participation, football athletes exhibited significantly more voxels in each of the categories, relative to controls. Of particular concern is that voxels exhibiting jointly decreased FA and MD—a change typically associated with cell death—were observed at a significantly higher rate within football athletes than non-contact athletes. This finding suggests that rHAEs may increase the incidence of cell death, and argues for the greater adoption of methods aimed at reducing mechanical loading on the brain from rHAEs, both through reduction of the number of HAEs, and development of better protective equipment.</div><div><br></div><div>Rugby is a sport that is very similar to football in terms of physicality and overall objective, but there are marked differences in protective equipment and style of play. These differences in protective equipment result in different tackling rules and styles between the two sports that may influence the effect repetitive HAEs can have on neurological health. Therefore, the HAEs experienced over the course of the season by New Zealand collegiate (ages 16+) rugby athletes were characterized. The number of HAEs were compared by position (forward vs. backs) and the peak translation acceleration (PTA) of the HAE was analyzed by position, possession (offense vs. defense), and cause of HAE (tackle vs. ruck). Forwards (although not significantly) tended to sustain more HAEs than backs, but there were no differences in the magnitude of the HAEs by any of the types of comparisons. However, when considering possession and type of HAE simultaneously, it was found that HAEs in a defensive ruck are more severe than those sustained in an offensive ruck. This could be a potential place to work on player technique to reduce the PTA during these situations.</div><div><br></div><div>There are numerous studies that have utilized accelerometers to quantify head motion during a contact event, but a current gap in the field is quantification of the impact force. In order to capture high force events, an instrumented helmet using strain was built to capture this data. Strain gauges were adhered to the inside of a Riddell Speedflex helmet shell and then mounted onto a Hybrid III Headform for testing. The helmet was hit at four different locations (front, right, back, and left) and at different impulse ranges (2-5 Ns, 5-8 Ns, 8-11 Ns, and 11+ Ns). The strain gauges were able to classify the location of the hit with about 95% accuracy and were correlated the impact peak force and impulse. This suggests that it is possible to build an instrumented helmet to be worn by a football player during collision events to capture real impact force and location data.</div>

Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood–brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood–brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti- and pro-inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age-matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro-inflammatory gene, HLA-DR, were significantly reduced in gray matter and expression levels of the anti-inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro-inflammatory (CD68, IL1β) and anti-inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro- or anti-inflammatory state in ASD. However, altered expression of pro- and anti-inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Lay Summary: The anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism.

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease.

BACKGROUND: White matter (WM) aberrations have been broadly characterized in schizophrenia using standard diffusion tensor imaging (DTI) techniques. The present study aims to distinguish WM alterations in the early course of schizophrenia using advanced diffusion measures of free-water corrected fractional anisotropy (FAt) and free-water fractional volume (FW), in addition to examining their association with neurocognition, social cognition, and clinical measures. We report baseline results from a longitudinal study investigating the effects of cognitive enhancement therapy (CET) on brain structure and function in schizophrenia. METHODS: The sample consisted of 46 early course schizophrenia patients and 20 healthy controls. Diffusion-weighted images were processed using a free-water imaging pipeline, that separately models diffusion of water in tissue (FAt) and the extracellular space (FW). Tract-Based Spatial Statistics was performed on the FAt and FW diffusion tensor maps and average measures from 24 bilateral regions of interest (ROIs) were extracted. We examined WM structural differences between patients and controls and further investigated WM relations to neurocognition, social cognition, and clinical measures specifically in schizophrenia. RESULTS: Patients showed significant FAt reductions in the body of the corpus callosum, posterior thalamic radiation (PTR), cingulate gyrus, anterior corona radiata, corpus callosum, and corona radiata and FW elevations in the posterior corona radiata (PCR), uncinate fasciculus (UNC), and PTR compared to controls. For patients, positive correlations between FAt and working memory were observed in the PCR and fornix & stria terminalis (FXST). Negative associations between FW and attention/vigilance were observed in the UNC. Positive correlations between FAt and theory of mind (ToM) were observed in average whole-brain and FXST. Negative associations between FW and ToM were observed in average whole-brain and PCR. Positive correlations between FW and negative symptom severity were observed in the external capsule. CONCLUSION: Using free-water imaging, we report WM aberrations and FW elevations in the early course of schizophrenia in addition to neural correlates associated with cognition and clinical measures. Future investigations on the longitudinal effects of CET are warranted for a greater understanding of the underlying neural correlates of clinical manifestations in schizophrenia. / 2020-06-14T00:00:00Z

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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19554号 / 医博第4061号 / 新制||医||1012(附属図書館) / 32590 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 渡邉 大, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Recent studies have found associations between prolonged stress response and white matter (WM) microstructure in individuals with schizophrenia, as well as correlations between early life trauma and WM integrity in individuals with schizophrenia and non-psychiatric controls; however, psychosocial correlates of WM dysfunction have not yet been adequately explored in individuals experiencing attenuated psychotic symptoms (APS, subthreshold versions of positive psychotic symptoms). This study examines WM microstructure using traditional and free-water corrected diffusion metrics within a community sample of 66 16 to 30-year-olds experiencing a range of APS to examine the contribution of perceived stress and childhood trauma to the relationship between APS and WM abnormalities, as well as examine the moderating influence of sex assigned at birth (herein referred to as sex) to these relationships. We found that overall symptom severity on the Structured Interview for Psychosis-risk Syndromes (SIPS) was associated with higher extracellular free-water (FW) across the whole brain, lower free-water corrected fractional anisotropy values (FAT), and higher free-water corrected radial diffusivity (RDT). Further, childhood trauma significantly moderated the relationship between SIPS scores and both FAT and RDT, controlling for biological sex at birth, such that in the presence of APS, childhood trauma was associated with higher FAT and lower RDT, and in lower APS the opposite pattern was seen, with childhood trauma associated with lower FAT and lower RDT. After stratifying for sex, childhood trauma moderated the SIPS – FAT and RDT relationships in males similar to findings in the whole sample, though this relationship was not present in females. Perceived stress was not a significant moderator in the total sample, though was a significant moderator of the APS – FA relationship in males only. This study represents an important step toward identifying mechanisms for WM dysfunction within individuals with psychosis spectrum disorders, as well as identifying important targets for interventions. / Psychology