Multisensory mechanisms of body ownership and self-location

Having an accurate sense of the spatial boundaries of the body is a prerequisite for interacting with the environment and is thus essential for the survival of any organism with a central nervous system. Every second, our brain receives a staggering amount of information from the body across different sensory channels, each of which features a certain degree of noise. Despite the complexity of the incoming multisensory signals, the brain manages to construct and maintain a stable representation of our own body and its spatial relationships to the external environment. This natural “in-body” experience is such a fundamental subjective feeling that most of us take it for granted. However, patients with lesions in particular brain areas can experience profound disturbances in their normal sense of ownership over their body (somatoparaphrenia) or lose the feeling of being located inside their physical body (out-of-body experiences), suggesting that our “in-body” experience depends on intact neural circuitry in the temporal, frontal, and parietal brain regions. The question at the heart of this thesis relates to how the brain combines visual, tactile, and proprioceptive signals to build an internal representation of the bodily self in space. Over the past two decades, perceptual body illusions have become an important tool for studying the mechanisms underlying our sense of body ownership and self-location. The most influential of these illusions is the rubber hand illusion, in which ownership of an artificial limb is induced via the synchronous stroking of a rubber hand and an individual’s hidden real hand. Studies of this illusion have shown that multisensory integration within the peripersonal space is a key mechanism for bodily self-attribution. In Study I, we showed that the default sense of ownership of one’s real hand, not just the sense of rubber hand ownership, also depends on spatial and temporal multisensory congruence principles implemented in fronto-parietal brain regions. In Studies II and III, we characterized two novel perceptual illusions that provide strong support for the notion that multisensory integration within the peripersonal space is intimately related to the sense of limb ownership, and we examine the role of vision in this process. In Study IV, we investigated a fullbody version of the rubber hand illusion—the “out-of-body illusion”—and show that it can be used to induce predictable changes in one’s sense of self-location and body ownership. Finally, in Study V, we used the out-of-body illusion to “perceptually teleport” participants during brain imaging and identify activity patterns specific to the sense of self-location in a given position in space. Together, these findings shed light on the role of multisensory integration in building the experience of the bodily self in space and provide initial evidence for how representations of body ownership and self-location interact in the brain

Immune cell composition and cytokine expression in the pregnant and non-pregnant uterus

The success of implantation and further development of the embryo is heavily dependent on the endometrial immune cell composition and its ability to communicate with fetal semi-allogeneic trophoblast cells. Although our understanding of the immune cell population in the uterus has improved, its precise role in normal reproduction and reproductive disorders is still not fully resolved. Here, we examined immune cells and signal molecules derived from the endometrium around the time of implantation, in postmenopause, and in early pregnancy. In study I, we analyzed cytokine and chemokine characteristics in menstrual blood from healthy nulliparous women with regular menstrual cycles, both before and after luteal phase endometrial scratching. The menstrual blood cytokine profile showed little interindividual variation and differed distinctly from peripheral blood. Endometrial scratching did not affect the cytokine profile in menstrual blood. Study II examined the dynamics of endometrial MAIT cells in various reproductive states, including pre- and postmenopausal endometrium and in first trimester decidua. We also evaluated the impact of genetic and environmental factors on the endometrial MAIT cell population by comparing the size of the MAIT cell compartment in menstrual and peripheral blood from monozygotic twins. Additionally, we examined the tissue-residency of endometrial MAIT cells by using transplanted uteri as a model. Finally, we assessed the ability of MAIT cells to react against N. gonorrhoeae, a pathogen known to infect the female genital tract and pose a growing threat of antibiotic resistance. We found that the frequency of endometrial MAIT cells remained stable throughout the different reproductive stages of the endometrium, and that they exhibited both a more activated state and a tissue-resident phenotype compared to their peripheral counterparts. However, in the transplanted uteri, only MAIT cells positive for the recipients HLA were present within the uterus, suggesting that endometrial MAIT cells are transiently tissue-resident and replenished over time from the circulation. Last, we demonstrated that MAIT cells are functional and respond to N. gonorrhoeae. In study III, we investigated the immune cell characteristics in vaginal blood from women with first trimester pregnancy bleeding and associated findings with pregnancy outcome (miscarriage/ not miscarriage). Saliva and serum proteome was analyzed and correlated to vaginal immune cell phenotype and outcome of pregnancy. We found that vaginal blood contained all main immune cell lineages, and that a higher frequency of tissue-resident CD49a+ NK cells in vaginal blood was associated with pregnancy loss. The frequency of vaginal blood tissue-resident NK cells correlated with levels of several maternal serum proteins. In summary, this thesis provides valuable new insights into reproductive physiology and sheds light on various aspects of the uterine immune system. The findings from this research can be used for future comparisons with reproductive pathological states that may involve altered cytokine and immune cell composition

Imaging of the brain opioid system in amphetamine dependence

Amphetamine dependence is a global health problem, often giving rise to severe medical and social complications in affected individuals. Unfortunately, there is still limited evidence for any specific treatment that would help amphetamine dependent patients to avoid relapse. One of the most promising treatments is the opioid antagonist naltrexone, which has been shown to attenuate the subjective effects of amphetamine and in some randomized clinical trials also reduce the risk of relapse. The aim of this thesis work was to investigate the mechanism of action of naltrexone for amphetamine dependence, in order to better understand the neurobiology involved and facilitate further treatment development. We used the neuroimaging techniques positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to study these processes in the human brain. In Study I, we tested the hypothesis that an amphetamine injection causes a release of endogenous opioids in the brain, which might explain why an opioid antagonist such as naltrexone attenuates the subjective effects of amphetamine. However, using PET and the µ opioid radioligand 11C-carfentanil, we found no evidence of such an amphetamine-induced opioid release in healthy human subjects without any previous experience of amphetamine. Study II investigated whether naltrexone pre-treatment affects the dopamine release that occurs in the brain after amphetamine intake, an effect that some previous studies have found to correlate with the subjective effects of amphetamine. If naltrexone were to attenuate this dopamine release, it might help to explain why it affects the subjective effects of amphetamine. In a first experiment, we used PET and the radioligand 11C-raclopride, but found no evidence that naltrexone affected amphetamine-induced dopamine release in healthy, previously amphetamine-naïve human subjects. We proceeded with experiments using in vivo microdialysis in rats, where similar results were found: pre-treatment with naltrexone did not affect the dopamine release caused by an acute amphetamine dose in rats without previous exposure to amphetamine. However, in rats that had been treated with amphetamine for a longer time period, naltrexone did attenuate the dopamine release when amphetamine was reinstated, suggesting that the brain opioid system might be involved in the adaptations to chronic amphetamine exposure. In Study III, we investigated the effects of naltrexone on cue reactivity, i.e. the reaction of substance dependent patients to environmental stimuli reminding them of drug use. This process is interesting as it can be an important trigger of relapse. For this study, we included 40 men with severe, intravenous amphetamine dependence, who received one oral dose of naltrexone or placebo and then underwent an fMRI examination including exposure to drugrelated and neutral film clips. The hypothesis was that the drug-related films would cause a subjective craving reaction and increase the activity of a number of motivationally relevant brain regions, and that naltrexone would attenuate this reactivity. We found that the films did cause strong craving and wide-spread fMRI activations, but there was no evidence of any effect of naltrexone on these measures. Study IV investigated the proposed phenomenon of subliminal cue reactivity, where the brains of substance dependent patients have been reported to react specifically to drug-related pictures, even when the pictures are presented very fast and with a backward mask, so that they never reach conscious awareness. In our study, which used the same patient sample as Study III and 30 healthy controls, we found no evidence of any subliminal drug cue reactivity. Upon closer examination of the earlier studies, we found that the reliability of their statistical inferences could be questioned, which together with our negative results suggest that there is no strong evidence for subliminal cue reactivity in addiction. In summary, the studies of this thesis have not corroborated the hypotheses we started out with regarding the mechanisms behind naltrexone’s effects in amphetamine dependence. Instead, the results have inspired new hypotheses, for example regarding how the interplay between the brain dopamine and opioid systems may change with long-term amphetamine use. These studies have also highlighted methodological challenges that may help to improve future neuroimaging studies of addiction

Alcohol Dependence Associated with Increased Utilitarian Moral Judgment: A Case Control Study

Recent studies indicate that emotional processes, mediated by the ventromedial prefrontal cortex (VMPC), are of great importance for moral judgment. Neurological patients with VMPC dysfunction have been shown to generate increased utilitarian moral judgments, i.e. are more likely to endorse emotionally aversive actions in order to maximize aggregate welfare, when faced with emotionally salient personal moral dilemmas. Patients with alcohol dependence (AD) also exhibit impairments in functions mediated by the prefrontal cortex, but whether they exhibit increased utilitarian moral reasoning has not previously been investigated. The aim of this study was to investigate moral judgment in AD patients (n = 20) compared to healthy controls (n = 20) matched by sex, age and education years. Each subject responded to a battery of 50 hypothetical dilemmas categorized as non-moral, moral impersonal and moral personal. They also responded to a questionnaire evaluating explicit knowledge of social and moral norms. Results confirmed our hypothesis that AD patients generated increased utilitarian moral judgment compared to controls when faced with moral personal dilemmas. Crucially, there was no difference in their responses to non-moral or impersonal moral dilemmas, nor knowledge of explicit social and moral norms. One possible explanation is that damage to the VMPC, caused by long term repeated exposure to alcohol results in emotional dysfunction, predisposing to utilitarian moral judgment. This work elucidates a novel aspect of the neuropsychological profile of AD patients, namely a tendency to generate utilitarian moral judgment when faced with emotionally salient moral personal dilemmas

Decoding illusory self-location from activity in the human hippocampus

Decades of research have demonstrated a role for the hippocampus in spatial navigation and episodic and spatial memory. However, empirical evidence linking hippocampal activity to the perceptual experience of being physically located at a particular place in the environment is lacking. In this study, we used a multisensory out-of-body illusion to perceptually ‘teleport’ six healthy participants between two different locations in the scanner room during high-resolution functional magnetic resonance imaging (fMRI). The participants were fitted with MRI-compatible head-mounted displays that changed their first-person visual perspective to that of a pair of cameras placed in one of two corners of the scanner room. To elicit the illusion of being physically located in this position, we delivered synchronous visuo-tactile stimulation in the form of an object moving toward the cameras coupled with touches applied to the participant’s chest. Asynchronous visuo-tactile stimulation did not induce the illusion and served as a control condition. We found that illusory self-location could be successfully decoded from patterns of activity in the hippocampus in all of the participants in the synchronous (P 0.05). At the group-level, the decoding accuracy was significantly higher in the synchronous than in the asynchronous condition (P = 0.012). These findings associate hippocampal activity with the perceived location of the bodily self in space, which suggests that the human hippocampus is involved not only in spatial navigation and memory but also in the construction of our sense of bodily self-location

In situ primary production of Fucus vesiculosus and Cladophora glomerata

The primary production of two of the most commonly distributed benthic algae in the Baltic proper was measured using different in situ methods (bottles, plastic bags, 14C and O2) during summer. Results on exudation and heterotrophic activity of these exudates have been worked out for Fucus. Low primary production and exudation values are found, while the total bacterial activity seems to be high compared to the net primary production

Body perception in newborns

Body ownership and awareness has recently become an active topic of research in adults using paradigms such as the “rubber hand illusion” and “enfacement” [1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11]. These studies show that visual, tactile, postural, and anatomical information all contribute to the sense of body ownership in adults [12]. While some hypothesize body perception from birth [13], others have speculated on the importance of postnatal experience [14 and 15]. Through studying body perception in newborns, we can directly investigate the factors involved prior to significant postnatal experience. To address this issue, we measured the looking behavior of newborns presented with visual-tactile synchronous and asynchronous cues, under conditions in which the visual information was either an upright (body-related stimulus; experiment 1) or inverted (non-body-related stimulus; experiment 2) infant face. We found that newborns preferred to look at the synchronous condition compared to the asynchronous condition, but only when the visual stimulus was body related. These results are in line with findings from adults and demonstrate that human newborns detect intersensory synchrony when related to their own bodies, consistent with the basic processes underlying body perception being present at birth

Modulating Anti-MicroRNA-21 Activity and Specificity Using Oligonucleotide Derivatives and Length Optimization

MicroRNAs are short, endogenous RNAs that direct posttranscriptional regulation of gene expression vital for many developmental and cellular functions. Implicated in the pathogenesis of several human diseases, this group of RNAs provides interesting targets for therapeutic intervention. Anti-microRNA oligonucleotides constitute a class of synthetic antisense oligonucleotides used to interfere with microRNAs. In this study, we investigate the effects of chemical modifications and truncations on activity and specificity of anti-microRNA oligonucleotides targeting microRNA-21. We observed an increased activity but reduced specificity when incorporating locked nucleic acid monomers, whereas the opposite was observed when introducing unlocked nucleic acid monomers. Our data suggest that phosphorothioate anti-microRNA oligonucleotides yield a greater activity than their phosphodiester counterparts and that a moderate truncation of the anti-microRNA oligonucleotide improves specificity without significantly losing activity. These results provide useful insights for design of anti-microRNA oligonucleotides to achieve both high activity as well as efficient mismatch discrimination