京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20666号 / 医博第4276号 / 新制||医||1024(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 伊佐 正, 教授 富樫 かおり, 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

Each year, about 800,000 individuals die by suicide globally, affecting millions more. Mitigating suicide risks by targeting modifiable factors such as the sleep disturbances of insomnia and nightmares, which are prevalent and linked to suicidality is important. This study investigated the structural and functional brain differences related to sleep disturbances and suicidality, with the anterior cingulate (caudal and rostral), insula, middle frontal gyrus, posterior cingulate, thalamus, amygdala, and orbitofrontal cortex as seed regions. Participants had no history of suicidal ideation (NSI; n=43) or suicidal ideation within the past two weeks (SI; n=25). Measures for analyses included the Insomnia Severity Index (ISI), Disturbing Dream and Nightmare Severity Index (DDNSI), and Frequency of Suicidal Ideation Inventory (FSII). The relationships between group (control vs suicidal ideation), structural measurements (cortical surface area, cortical thickness, gray matter volume), insomnia and nightmares across the eight regions in each hemisphere were examined. Functional connectivity-change differences were measured across wake and sleep with the eight regions as seeds. The SI group had smaller cortical surface area and gray matter volumes in the left insula (t= 2.58, p = 0.012; t = 2.44, p = 0.017); however, not after adjusting for multiple comparisons. ISI and FSII total scores correlated with each other and the surface area and gray matter volume of the left insula. In a mediation model, ISI total score was significantly related to insula surface area and FSII total score (p = 0.023; p =0.027), but the insula surface area was not significantly associated with FSII total score (p = 0.075). The indirect effect of ISI on FSII through the left insula surface area was not significant (p =0.161). The SI group had smaller changes from wake to sleep than the NSI group in the functional connectivity of the right thalamus to the left and right superior/middle temporal regions. Other neurological mechanisms could be at play as only the cortical surface area and gray matter volume in the left insula had implied differences between groups and the structural differences did not mediate the relationship between insomnia and suicidality. Smaller functional connectivity-changes differences across wake and sleep for SI compared to NSI, potentially indicate deficits in auditory inhibition.

Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.

Background: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. Method. We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). Results: During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. Conclusions: This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobiaspecific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.

L'insula est une structure complexe impliquée dans une variété de fonctions. Les études de connectivité par traçage chez les primates non humains ont révélé une multitude de connexions corticales entre l'insula et les lobes frontal (cortex orbitofrontal, cortex préfrontal, régions cingulaires, aire motrice supplémentaire), pariétal (cortex somatosensoriel primaire et secondaire) et temporal (pôle temporal, cortex auditif, cortex prorhinal et entorhinal). Les études de tractographie chez l'humain ont révélé des connexions structurelles similaires, mais n'ont pas rapporté de connexion avec le cortex cingulaire, malgré que cette structure soit reconnue comme étant fonctionnellement connectée à l’insula. Ce projet vise à approfondir la recherche sur la connectivité structurelle entre ces deux structures ainsi que d'autres régions connues comme étant fonctionnellement connectées à l'insula, à l'aide d'un échantillon plus grand et des plus récentes méthodes en tractographie par l’imagerie à haute résolution de diffusion angulaire basée sur des a priori anatomiques. En analysant les données de 46 participants adultes en bonne santé, notre étude rapporte un large éventail de connexions entre l’insula et les lobes frontal, temporal, pariétal et occipital ainsi que les régions limbiques, suivant un patron d’organisation rostrocaudal. Notamment, nous démontrons pour la première fois une connexion structurelle claire entre l’insula et les gyri cingulaire, parahippocampique, supramarginal et angulaire ainsi que le précunéus et les régions occipitales. / The insula is a complex structure involved in a wide range of functions. Tracing studies on non-human primates reveal a wide array of cortical connections in the frontal (orbitofrontal and prefrontal cortices, cingulate areas, and supplementary motor area), parietal (primary and secondary somatosensory cortices) and temporal (temporal pole, auditory, prorhinal and entorhinal cortices) lobes. However, recent human tractography studies have not observed connections between the insula and the cingulate cortices, although these structures are thought to be functionally intimately connected. In this work, we try to unravel the structural connectivity between these regions and other known functionally connected structures, benefiting from a higher number of subjects and the latest state-of-the-art high angular resolution diffusion imaging (HARDI) tractography algorithms with anatomical priors. By performing a HARDI tractography analysis on 46 young normal adults, our study reveals a wide array of connections between the insula and the frontal, temporal, parietal and occipital lobes as well as limbic regions, with a rostro-caudal organization in line with tracing studies in macaques. Notably, we reveal for the first time in humans a clear structural connectivity between the insula and the cingulate, parahippocampal, supramarginal and angular gyri as well as the precuneus and occipital regions.

Orientadora: Profª Drª Raquel Vecchio Fornari / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Neurociência e Cognição, 2015. / O cortex insular (CI), ou insula, conquistou nos ultimos anos um lugar de destaque na area cientifica por seu suposto envolvimento em processos emocionais e cognitivos. No rato, como nos seres humanos, o CI pode ser dividido em duas sub-regioes funcionalmente heterogeneas. Embora a maioria dos estudos realizados em animais tenha mostrado um envolvimento da regiao mais rostral (CI anterior) na memoria gustativa, outros sugerem um papel mais amplo, abrangendo desde o reconhecimento de objetos ate o processamento de memorias espaciais e aversivas. A regiao mais caudal (CI posterior), por sua vez, recebe aferencias multissensoriais e supoe-se que esteja envolvida em processamento multissensorial e nociceptivo. Entretanto, pouquissimos trabalhos avaliaram a participacao dessa sub-regiao posterior em tarefas de memoria, com resultados inconclusivos. Nao havia, ate o momento, nenhum trabalho que tivesse investigado isoladamente o papel de ambas as sub-regioes do CI na consolidacao da memoria emocional. Portanto, o objetivo deste estudo foi investigar os efeitos da inativacao temporaria do CI anterior e posterior sobre a consolidacao da memoria de medo de tarefas de condicionamento de medo ao contexto e ao som. Ratos Wistar de 3 meses de idade passaram por cirurgia estereotaxica para implante de canulas-guia bilaterais no CI anterior ou posterior. Os animais tiveram pelo menos 7 dias de recuperacao e foram manipulados por 3 dias antes do inicio do procedimento comportamental. Para o treino de condicionamento de medo ao contexto e ao som, os ratos foram colocados individualmente em um caixa de condicionamento. Apos 120 segundos de livre exploracao, um som (90 decibeis, 2 kHz) foi emitido por 30 segundos, co-terminando com um choque nas patas (0,7 mA, 1s). Imediatamente apos, cada rato recebeu uma microinfusao bilateral de muscimol (agonista gabaergico, 0,5¿Êg/0,5¿ÊL por hemisferio) ou salina (grupo controle). O teste de condicionamento de medo ao contexto (CMC) ocorreu 48 horas apos o treino e consistiu na re-exposicao a caixa de condicionamento por 5 minutos, sem apresentacao de som ou choque. 24 horas depois, os mesmos animais foram submetidos ao teste de condicionamento de medo ao som (CMS), o qual ocorreu em uma caixa modificada, com duracao de 5 minutos. Ao final do segundo e terceiro minutos, o mesmo estimulo sonoro apresentado no treino foi emitido por 30 segundos. O tempo de congelamento e o comportamento motor foram utilizados como medidas de condicionamento. No CMS, os ratos que receberam a microinfusao de muscimol no CI anterior e posterior apresentaram uma media de tempo de congelamento menor durante o periodo pos-som. Entretanto, no CMC nao houve diferencas entre grupos para ambas as subregioes do CI. Portanto, os resultados deste estudo indicam que a inativacao pos-treino do CI como um todo prejudica exclusivamente o CMS. Entretanto, o prejuizo deste tipo de memoria, provocado pela inativacao do CI posterior, foi maior, evidenciando, portanto, que esta subregiao esta mais importantemente envolvida na circuitaria neural responsavel pela consolidacao do medo condicionado a um estimulo sonoro discreto. / The insular cortex (IC), or insula, has achieved over the last years an eminent position in the scientific literature due to its involvement in emotional and cognitive processes. In the rat, as in humans, the IC can be divided into two functionally heterogeneous sub-regions. Although most animal studies have shown an involvement of the rostral subregion (anterior IC) in gustatory memory, others suggest a broader role in memory, ranging from object recognition to the processing of spatial and aversive memories. In addition, even though the most caudal area (posterior IC) seems to be involved in multisensory and nociceptive processing, very few studies have evaluated its role in mnemonic processes and the results so far are unclear. Nevertheless, no work, to the best of our knowledge, had investigated the specific role of both sub-regions of the IC on consolidation of fear conditioning tasks. Thus, the aim of the present study was to investigate the effects of temporary inactivation of the anterior and posterior IC on memory consolidation of contextual and tone fear conditioning tasks. 3-month-old male Wistar rats underwent stereotaxic surgery for implantation of bilateral guide cannulae aimed directly above the anterior or posterior IC. The animals were allowed at least 7 days of recovery and were handled once a day for 3 days prior to behavioral sessions. For the contextual and tone fear conditioning training session, the rats were individually placed in the conditioning box. After 120 seconds of free exploration, a tone (90 decibels, 2 kHz) was delivered for 30 seconds, coterminating with a footshock (0.7 mA, 1 s). Immediately after, each rat received a bilateral microinjection of muscimol (GABAergic agonist, 0.5 ìg/0.5ìL by hemisphere) or saline (control group) into the intended IC subregion. The contextual fear conditioning test (CFC) was performed 48 hours after training and consisted in the re-exposure to the conditioning box for 5 minutes, without delivery of tone and shock. After 24 hours, the same animals were submitted to tone fear conditioning test (TFC), which occurred in a modified chamber, for 5 minutes. At the end of the second and third minutes, the same tone stimulus presented in the training session was delivered for 30 seconds. Freezing time and motion behavior were used as measures of conditioning. In TFC, the rats that had received muscimol microinfusion into the anterior and posterior IC displayed a lower freezing time during the post-tone period. However, for both IC subregions, there were no differences between groups in the CFC. Thus, our findings indicate that the posttraining inactivation of both IC subregions impaired the TFC. However, the impairment in this kind of memory, caused by the the inactivation of the posterior IC, was higher, thus, highlighting that this subregion is more importantly involved in the neural circuitry related to the consolidation of the discrete tone conditioned fear.

ABSTRACT Gliomas are the most common type of brain tumours and are often diffusely localised in areas that give permanent functional symptoms, so called eloquent areas. These areas partly control speech and language. Low-grade glioma (LGG) is the most suitable type of tumour for awake surgery. By performing surgery while the patient is awake, intra-operative testing of language and speech is possible and a more secure tumour resection can be performed. Patients that are to undergo such surgery execute a pre-operative speech and language testing, done by a speech and language pathologist, which is later used as a reference for the intra- and post-operative assessment. In this study the pre- and post-operative results for 20 patients with gliomas, who underwent awake surgery on 23 occasions at the Akademiska hospital in Uppsala from June 2013 until August 2015 were analysed. The aim of this study was to evaluate how the tumour resection affected speech and language. Furthermore, possible correlations between language deficits and tumour localisation were investigated. The results showed considerable variations in whether the patients improved and/or deteriorated. Overall, more patients deteriorated than improved. More pronounced deficits were shown for naming and verbal fluency pre- and post-operatively. A correlation analysis showed that patients with a tumour located in insula had greater difficulties with naming than patients with other tumour locations. This study provides an evaluation of the language outcomes of patients who underwent awake surgery in Uppsala. Additionally, the study resulted in an overview of the development of speech and language pathologists’ assessments since the start of awake surgery in 2013, and specific recommendations for improvement.   Keywords: Low-grade gliomas, awake surgery, pre- and post-operative speech and language testing, speech and language pathology, naming, verbal fluency, insula SAMMANFATTNING Gliom är den vanligaste typen av hjärntumör och är ofta diffust lokaliserad i områden som ger bestående funktionsnedsättning vid skada, så kallade elokventa områden. Dessa områden kontrollerar bland annat tal och språk. Av dessa är det de lågmaligna/låggradiga gliomen (LGG) som oftast är aktuella för resektion i vaket tillstånd. Genom att utföra operationen när patienten är vaken tillåts intraoperativ testning av tal och språk vilket leder till säkrare resektion. Alla patienter som ska genomgå denna typ av operation utför preoperativ tal- och språkbedömning hos logoped, som senare används som referenspunkt för den intra- och postoperativa bedömningen. I denna studie analyserades pre- och postoperativa resultat för 20 patienter med gliom som opererats vid 23 olika tillfällen på Akademiska sjukhuset i Uppsala sedan verksamheten startade juni 2013. Två frågeställningar skulle besvaras: Hur har tumörresektionen påverkat tal- och språkförmågan hos patienter som genomgått kirurgi i vaket tillstånd? Finns det något samband mellan språkliga symptom och tumörlokalisation? Resultatet visade stora variationer i huruvida patienterna förbättrades och/eller försämrades i sin tal- och språkfunktion efter operation. Generellt noterades dock fler försämringar än förbättringar. Benämning och verbalt ordflöde var de två parametrar där störst svårigheter påvisades både pre- och postoperativt. Korrelationsanalys visade att patienter med tumörer i insula hade större svårigheter med benämning än patienter med övriga tumörlokalisationer. Förutom att beskriva det språkliga utfallet för de patienter som genomgått kirurgi i vaket tillstånd så har denna studie resulterat i en översikt av hur logopedbedömningarna sett ut pre- och postoperativt sedan vakenkirurgin infördes i Uppsala, och även förslag på hur de kan förbättras i framtiden.   Nyckelord: Lågmaligna gliom, vakenkirurgi, pre- och postoperativ tal- och språkbedömning, logopedi, benämning, verbalt ordflöde, insula

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Can the brain register the emotional valence of brief exposures of complex natural stimuli under conditions of forward and backward masking, and under conditions of attentional competition between foveal and peripheral stimuli? To address this question, three experiments were conducted. The first, a behavioural experiment, measured subjective valence of response (pleasant vs unpleasant) to test the perception of the valence of natural images in brief, masked exposures in a forward and backward masking paradigm. Images were chosen from the International Affective Picture System (IAPS) series. After correction for response bias, responses to the majority of target stimuli were concordant with the IAPS ratings at better than chance, even when the presence of the target was undetected. Using functional magnetic resonance imaging (fMRI), the effects of IAPS valence and stimulus category were objectively measured on nine regions of interest (ROIs) using the same strict temporal restrictions in a similar masking design. Evidence of affective processing close to or below conscious threshold was apparent in some of the ROIs. To further this line of enquiry, a second fMRI experiment mapping the same ROIs and using the same stimuli were presented in a foveal (‘attended’) peripheral (‘to-be-ignored’) paradigm (small image superimposed in the centre of a large image of the same category, but opposite valence) to investigate spatial parameters and limitations of attention. Results are interpreted as showing both valence and category specific effects of ‘to-be-ignored’ images in the periphery. These results are discussed in light of theories of the limitations of attentional capacity and the speed in which we process natural images, providing new evidence of the breadth of variety in the types of affective visual stimuli we are able to process close to the threshold of conscious perception.