京都大学 / 新制・課程博士 / 博士(医学) / 甲第23069号 / 医博第4696号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 林 康紀, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In addition to mood symptoms, major depressive disorder (MDD) is characterized by cognitive impairments that can have detrimental impacts on quality of life and daily function, and have been found to persist into remission. In particular, altered affective cognition (e.g. biased attention to negative stimuli) has been reported in MDD, and may continue into remission. Unfortunately, current pharmacotherapies do not adequately address cognitive dysfunction in acute or remitted MDD. Understanding the neurobiological underpinnings of affective cognitive dysfunction in remitted MDD may help inform the development of new interventions to address this lingering problem and the associated poorer functional outcomes. The triple network model posits that altered functioning of three key networks implicated in normal cognitive function – the default mode network (DMN), central executive network (CEN) and salience network (SN) – underlies cognitive dysfunction in a variety of psychiatric illnesses, including MDD. Though notable exceptions exist, work in acutely depressed MDD patients has found evidence of DMN hyperconnectivity, CEN hypoconnectivity and abberant SN connectivity both at rest and during the completion of various cognitive tasks. The evidence for triple network connectivity alterations persisting into remission is less robust, and warrants further investigation. Furthermore, there is a paucity of studies examining remitted MDD connectivity during affective tasks. As such, the primary objectives of this thesis were to: 1) compare resting-state and task triple network connectivity profiles in remitted MDD patients (rMDDs) and healthy volunteers (HVs) at rest, during an affective (emotional Stroop [eStroop]) task, and during rest vs. the task and, 2) assess the relationship between DMN and CEN connectivity and measures of daily functioning, quality of life and/or negative, self-relational rumination in the rMDD cohort. Behaviourally, there were findings of an affective attentional bias and impaired processing speed in the rMDD vs. HVs, as revealed by a computerized cognitive test battery. However, we found no evidence of DMN hyperconnectivity or CEN hyperconnectivity in the rMDD study sample. We did find evidence of altered intrinsic CEN and CEN-SN connectivity between the rest and task conditions that seemed driven by the rMDD sample, as well as positive CEN-DMN correlations across the entire sample both at rest and during the eStroop task. Suprisingly, we also found higher intrinsic DMN connectivity during the eStroop task vs. at rest across the whole sample. Finally, we found a positive relationship between task-based CEN connectivity and hopeless rumination, and a significant negative relationship between resting state and task-based DMN connectivity and psychosocial dysfunction in the rMDD sample. These findings contribute to our understanding of large-scale intrinsic network connectivity alterations during remitted depression, and their relationship to functional outcomes.

Title: Measuring electrical brain activity during stimulation of trigger zones from concept of Vojta principle Objectives: The aim of this study is to clarify whether there is a change in the electrical brain activity evaluated by the sLORETA program during the stimulation of trigger zones according to the Vojta concept. The source activity during stimulation of trigger zones was scanned from the scalp EEG and compared with the sLORETA program with the source activity measured at rest, before and after the stimulation of the trigger zones. Methods: The research was conducted on 11 healthy adult subjects. The entire research group is consisted of women aged in range 19-32. The data was obtained from the scalp EEG before, during and after stimulation of trigger zones according to Vojta concept. For each proband the measurement of resting EEG with both open and closed eyes (2 x 10 minutes) was first performed, then the measurements were taken during the stimulation of trigger zones with open and closed eyes (2 x 15 minutes). Finally, a resting EEG was measured, alternating open and closed eyes after five minutes (4 x 5 minutes). There was a pause of at least 15 minutes between each stimulation of trigger zones. The order of open and closed eyes during resting EEG and during stimulation of trigger...

This literature review examines the default mode network (DMN) and how its role in self related processing and narrative selfhood relates to well-being. The essay explores the DMN in three levels of activity: Firstly in normal function, where mind-wandering is positively correlated with dissatisfaction; Secondly its abnormal function in depression, characterized by excessive activity and rumination; Thirdly in its arguably improved function during mindfulness and meditation, where lower activity is associated with higher well-being, decreased mind-wandering and altered sense of self. The essay shows a relationship between the DMN and well-being, where higher activity correlates with lower well-being.

Feelings of social connection are important to maintain physical and psychological well-being. Perceived social isolation, or loneliness, is the subjective experience of feeling socially isolated and may be a direct threat to our health. During recent years, an increasing amount of people report high levels of loneliness, potentially brought on by the COVID-19 pandemic and its restrictions. Recent research suggests that the brain’s default mode network (DMN), a neural network active at wakeful rest, is related to these experiences. This paper aimed to systematically review alterations in the DMN in socially connected and lonely individuals. I searched PubMed and Scopus to find studies using self-report measures of social connection or loneliness, and functional or structural neuroimaging methods on healthy adults. Nine studies were included in this review. Generally, core regions of the DMN typically involved in episodic memory and self-referential processing showed increased activity in lonely individuals and decreased activity in socially connected individuals. These findings may reflect how lonely individuals ruminate about past social events while socially connected individuals attend less to the self. However, methodological heterogeneity between studieslimits the conclusions that can be drawn based on these results.

Rumination, or extensive mind wandering defines one of the key cognitive symptoms of major depressive disorder (MDD). Several symptoms included in the psychiatric disorder have been associated with altered connectivity within the large-scaled system default mode network (DMN). Although it’s well-known that antidepressant treatment, such as selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) tend to positively affect symptoms and alterations of MDD, results are inconsistent regarding DMN connectivity pre-and-post treatment. This systematic review aims to compile findings from studies investigating DMN connectivity in MDD patients’ pre-and post SSRI and SNRItreatment, and to find possible correlations with symptomatic improvements. Five articles were included for further analysis after the literature search in MEDLINE ESBSCO and Scopus. Main findings are in alignment with previous research and suggest both hypo-and hyper DMN connectivity at baseline in MDD patients, and connectivity patterns significantly similar to healthy controls following antidepressant treatment. Future research might consider placebo controlled trials for more diverse, and quantified results, and also consider further investigation on both first-line treatments and other promising antidepressants.

The use of biomarkers in Alzheimer’s disease (AD) has been fundamental for early diagnosis. Currently, biomarkers in use for clinical purposes assess the presence or quantify molecular markers of the disease, i.e., ß-amyloid or Tau protein, or quantify the medial-temporal atrophy caused by the disease. Neuroimaging techniques such as structural, functional and diffusion magnetic resonance imaging and positron-emission tomography have been essential in showing how Alzheimer’s disease pathology spreads within resting-state networks, ultimately impairing their functioning. However, neuroimaging techniques provide indirect measures that do not capture the physiological status of the affected cerebral tissues. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), are established techniques that can be used in combination to capture both the status of a target cortex and its connections through the brain through TMS-evoked potentials (TEPs). Therefore, TEPs have gained momentum as a possible novel AD biomarker. In the last decade, a specific five-phase framework for the development of novel AD biomarkers has been developed, with the goal of standardizing the steps needed to bring a measure from research to clinical practice. Phase 1 for TEPs, concerning the rationale of using them as a biomarker in AD, could be considered completed, while most of the research is now focusing on phase 2. In this phase, the ability of a measure to distinguish between healthy elderly individuals and AD patients is assessed, together with the reliability and replicability of the measure. In this thesis, we address several aims of phase 2 by testing whether early TEP responses could be used to differentiate between healthy elderly, prodromal, late-onset, and early-onset AD. Then, we test the sensitivity of TEPs to different preprocessing pipelines to assess their robustness. Third, we review the current literature on TEP reliability and describe which tests are missing for this measure to enter clinical practice. Finally, we propose a tool to promote replicability in noninvasive brain stimulation paradigms, such as TMS–EEG. We conclude that despite a solid rationale for the employment of TEPs in clinical practice, several methodological issues need to be addressed before TEPs can gain clinical utility.

A perda auditiva consiste na perda, parcial ou total, da capacidade de ouvir determinados sons e compreensão de palavras. De acordo com o Censo Demográco do ano de 2000, o Brasil apresenta aproximadamente 5.700.000 de indivíduos com surdez, sendo deste total aproximadamente 2 milhões de indivíduos possuidores de perda auditiva severa e profunda. Atualmente diversos estudos têm sido realizados a m de vericar a plasticidade neural e o processo de linguagem em indivíduos surdos, entretanto pouco se conhece acerca do funcionamento do cérebro em repouso, e.g. a rede de modo padrão. O objetivo deste estudo é observar e analisar como se manifesta a organização neuronal, tanto funcional quanto estrutural, em surdos, no estado de repouso. Foram utilizadas imagens fMRI, para a obtenção de dados a respeito do funcionamento cerebral em seu estado de repouso basal, e imagens DTI, a m de se determinar as conexões neuronais. Os dados dos mapas de conectividade funcional e estrutural foram comparados com os achados denidos para sujeitos ouvintes. Nossos achados ilustram que o indivíduo surdo têm maior suporte para a atenção dirigida à tomada de decisão, monitoramento ambiental baseado nos movimentos de objetos e também no controle motor e visual. Podemos armar que a privação auditiva não oferece barreiras intransponíveis para o convívio familiar ou social, sendo o indivíduo surdo tão produtivo e capaz quanto qualquer outro, desde que a abordagem linguística seja condizente com suas capacidades sensoriais. / Hearing loss consists of partial or total loss of the ability to hear certain sounds and comprehension of words. According to the Brazilian Demographic Census of the year 2000, there are approximately 5,700,000 deaf individuals, of which approximately 2 million of them have severe and profound hearing loss. Several studies have now been carried out to verify neural plasticity and the language process in deaf individuals, however little is known about the brain functioning at rest, e.g. the network in standard mode. The objective of this study is to observe and analyze how neuronal organization, both in terms of functional and structural brain networks, is manifested in deaf individuals at resting state. We used fMRI images to obtain data on brain functioning in its basal state of rest and DTI images in order to determine neural connections. The data from the functional and structural connectivity maps were compared with the dened ndings for hearing subjects. Our ndings illustrate that the deaf individual has greater support for attention directed to decision making, environmental monitoring based on movement of objects and also on motor and visual control. We can arm that hearing deprivation does not oer impossible barriers to family or social life, being the deaf individual as productive and capable as any other, since the linguistic approach is consistent with their sensorial capacities.

Les situations de contact interpersonnel participeraient à la construction d’un sens basique du soi durant l’enfance, et de nos représentations de soi tout au long de la vie. Bien que l’on retrouve cette hypothèse de manière répandue dans la littérature, elle n’a été que très peu investigué expérimentalement. Cette thèse teste cet effet potentiel chez l’adulte. Deux études combinant mesures électrophysiologiques et comportementales montrent une augmentation d’une forme minimale de conscience de soi –des informations afférentes provenant du corps– suite à un contact social. Cet effet est reproduit dans 3 modalités sensorielles (contact social visuel, auditif et tactile). Une 3ème étude en magnétoencéphalographie teste l’effet d’un contexte de contact interpersonnel multisensoriel accru (vs réduit), entre un expérimentateur et des participants, sur la connectivité fonctionnelle des réseaux cérébraux dits de repos, et sur le contenu des pensées des participants. Nos résultats mettent en évidence une augmentation des processus cérébraux et cognitifs orientés sur le soi sous une forme hautement intégrée, associée à une diminution des processus sensoriels orientés sur l’environnement extérieur, à la suite d’un contact social accru. Dans l’ensemble, nos résultats suggèrent que le contact social améliore plusieurs facettes de la représentation de soi, aussi bien des aspects corporels, que des aspects plus haut-niveau et intégrés du soi narratif. Nos interactions sociales tout au long de la vie pourraient ainsi induire un contexte cérébral et cognitif centré sur un soi multifacette qui favoriserait la conscience de soi, et la construction d’un sens de l’identité incarné et situé. / Situations of interpersonal contact could contribute to the construction of a basic sense of self during childhood and to self-representations through lifespan. Although this hypothesis is widespread in the literature, the effect of social contact on self-awareness has been rarely been investigated experimentally. The aim of this PhD thesis is to investigate such an effect in human adults. In two studies combining electrophysiological measurements and behavioural responses, we show an enhancement of a minimal form of self-awareness – i.e. of the afferent information arising from the body – following social contact. This is reproduced across three sensory modalities (visual, auditory and tactile social contact). In a third study, we use magnetoencephalography to test the effect of an increased (vs reduced) multisensory interpersonal contact context between an experimenter and participants, on the functional connectivity of resting-state networks and on the participants’ thought contents. Our results revealed an enhancement of self-oriented cognitive and brain processes in a highly integrated form, associated to a decrease in externally oriented sensory processes, as a result of the social context of increased interpersonal contact. Together, our results suggest that social contact enhances multiple facets of self-representation, including basic bodily aspects of a minimal self, as well as higher level and integrated aspects of a narrative self. Our social interactions throughout lifespan may thus induce a cerebral and cognitive context centred on a multifaceted self, which would foster self-awareness and the construction of an embodied and embedded sense of identity.

Although the hazards of prenatal exposure to addictive substances have been documented for decades, it continues to be a prevalent social and health concern today. Alcohol and cocaine are two commonly abused substances during pregnancy, often leading to behavioral and cognitive disorders in exposed children. At present, the relationship between teratogenic effects of prenatal alcohol exposure (PAE) and prenatal cocaine exposure (PCE) on the brain and observed behavioral outcomes is still unclear. A primary reason for this incomplete understanding is the lack of information regarding neuronal functioning in these populations. Functional MRI, which measures real-time brain activation in response to certain stimuli, can be utilized to bridge the gap between known structural damage and observed behavioral outcomes. This thesis aims to examine structural and functional alterations in PAE and PCE populations as compared to unexposed, socio-economic status-matched populations. As the PAE population is highly affected by structural dysmorphology, the applicability of a newly developed diffeomorphic image registration method to this population is examined. Additionally, task-positive and task-negative functional connectivity and activity are investigated in the PAE population, and related to underlying structural alterations. Neural correlates of global arousal and emotional regulation are investigated in the PCE population, as these behavioral outcomes are most notable. Similarly, functional connectivity and activation in task-positive and task-negative networks, as well as correlated structural measures, are examined in the PCE population. The diffeomorphic image registration algorithm was found to improve both structural and functional image registration for the PAE population. In the examination of specific deficits in arithmetic processing, poorer performance in the PAE group was attributed to a multi-level effect produced by altered structural and functional connectivity and functional activity in calculation and default mode networks. Baseline arousal levels were found to be higher in adolescents with PCE as compared to healthy controls (by altered default mode network functioning); emotional regulation also appeared to be affected in the PCE group by a prefrontal-amygdala structural and functional disconnect. The findings of this thesis give insights into the relationship between task-positive and task-negative duality and cognitive impairment, and contribute to a more comprehensive understanding of the spectrum of clinical disorders caused by prenatal exposure to alcohol and cocaine.