京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13372号 / 論医博第2209号 / 新制||医||1047(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 花川 隆, 教授 髙橋 良輔, 教授 小柳 義夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20803号 / 医博第4303号 / 新制||医||1025(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 平井 豊博, 教授 今中 雄一, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This systematic review aims to investigate the alterations in gray matter volume (GMV) observed in the brains of individuals diagnosed with post-traumatic stress disorder (PTSD) through the Clinical Administered PTSD scale (CAPS) using Voxel-Based Morphometry (VBM) as a method. PTSD is diagnosed when an individual meets all the criteria for PTSD as defined by the DSM, which includes having experienced or witnessed a traumatic event, experiencing intrusive symptoms such as flashbacks or nightmares, avoiding triggers related to the trauma, experiencing negative changes in mood and cognition, and experiencing changes in arousal and reactivity. Previous research investigating gray matter alterations in patients with PTSD has yielded heterogeneous findings. The review incorporates a comprehensive search and analysis of pertinent studies conducted between 1995 and the present. Diverse databases were scrutinized to identify articles that fulfilled the inclusion criteria. Ultimately, a total of seven articles meeting our inclusion criteria were included in this systematic review. The sample sizes ranged from 30 to 75 participants. The control groups in the chosen articles varied, some only had healthy controls (HC), while some had trauma-exposed controls (TC) or included both. The results consistently revealed a reduction in GMV predominantly in the hippocampus, with additional areas exhibiting decreased GMV such as the bilateral hypothalamus and left inferior parietal lobule, right middle temporal gyrus, right inferior temporal gyrus, and right fusiform gyrus, as well as the bilateral calcarine cortex, left dorsal anterior cingulate cortex, left anterior cingulate cortex, and bilateral insula.

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Background: Adolescence and young adulthood are particularly vulnerable periods for the development of mental health disorders, including bipolar disorder (BD). Mental health screening at universities could aid in the early identification of particularly at- risk individuals, with the long-term aim of providing early treatment interventions to improve clinical outcomes. However, further research into the identification of appropriate behavioral and biological markers for vulnerability to psychiatric disorders – as well as into the acceptability and efficacy of mental health screening - is warranted. Methods: Young adults were recruited via an already existing Internet-based mental health screening survey of undergraduate students at the University of Oxford. In Study 1, qualitative interviews of young adults with and without previous mental health problems were conducted to assess the acceptability and efficacy of mental health screening within a university setting. In Studies 2-5 we explored the hypotheses of altered emotional decision-making, reward processing and neurostructural integrity as behavioral and neurobiological markers for vulnerability to bipolar disorder via the study of young adults with a common bipolar phenotype (BPP) - some of whom meet diagnostic criteria for bipolar II or not-otherwise-specified disorder (BD II/NOS). To that end, we employed a diverse range of methodologies: alcohol challenge (Study 2); neuropsychological task performance (Study 3); functional magnetic resonance imaging (fMRI; Study 4); diffusion tensor imaging (DTI) and voxel-based morphometry (VBM; Study 5). Results: Findings from Study 1 suggest that young adults are willing to participate in mental health screening within a university setting, and that such screening may be used to offer subsequent treatment interventions. Taken together, findings from Studies 2 and 4 suggest a general blunted reward response among unmedicated young adults at increased risk for BD during euthymia, and additionally suggest pathophysiological similarities between BD and alcohol use disorders (AUDs) that may provide a causal link between the elevated co-occurrence rates of the two disorders. Finally, findings from Study 5 suggest widespread white matter microstructural alterations – which are likely to be neurodevelopmental in origin – among antipsychotic- and mood-stabilizer naïve young adults with BD II/NOS. Conclusions: These data support the hypothesis of neurodevelopmental alterations identifiable prior to significant clinical impairment among young adults at increased risk of – or already meeting DSM-IV criteria for – bipolar disorder. They also suggest that young adults in higher education are willing to participate in mental health screening. Future studies should aim to identify more specific markers for individual disorders such as BD.

Attention deficit/hyperactivity disorder (ADHD) is a common disease with a worldwide prevalence of 5% on preschool children. It has been reported that ADHD patients have volume variant in partial brain regions. Futhermore, functional magnetic resonance imaging have also been used to detect function variant possibility in particular brain regions. In the last decade, some researchers used diffusion MR imaging to investigate the abnormality of neural fibers in disease involved with central nervous system. In general, the diffusion anisotropy of white matter in both ADHD patients and healthy subjects can be estimated seperately to undergo inter-subject comparison. While previous studies often used the popular ICBM brain template (MNI152), this study applied a self-made template of Taiwan adolescents as the common space of image normailization. In this work, group comparison of diffusion fractional anisotropy was performing by using two methods, TBSS and VBM. Both manners found a decreased FA in white matter of ADHD subjects compared with normal control group. However, regions detected by different methods showed low reproducibility. The areas of significant difference include inferior longitudinal fasciculus¡Binternal capsule¡Bexternal capsule¡Bsuperior longitudinal fasciculus¡Boptic radiation¡Bsuperior frontal¡Bsuperior region of corona radiata¡Bcorticospinal tract¡Bposterior region of corona radiata / superior longitudinal fasciculus¡Bsuperior fronto-occipital fasciculus¡Banterior region of corona radiata¡Bgenu of corpus callosum nerve fibers.

Attention deficit hyperactivity disorder (ADHD) is a neurobehavior developmental disorder that affects around 7.5% of Taiwan children. With the use of magnetic resonance imaging , many results have been reported that ADHD patients have volume atrophy in gray matter and dysfunction in couples of cortical regions. In recent years, diffusion MR imaging with diffusion-sensitizing gradients has been used to investigate the abnormality of neural fibers in disease involved with central nervous system. In this study, the anisotropy of white matter in both ADHD patients and age-matched healthy subjects was estimated using diffusion tensor imaging to undergo inter-subject comparison. In this work, a significant decrease (FWE-corrected p-value <0.05) of FA values has been found in white matter of adolescents diagnosed as ADHD patients, compared with normal controls group. The areas that confirmed by two different algorithms of inter-subject comparison are mainly diffused on white matter region, including middle cerebellar peduncle, left inferior longitudinal fasciculus, internal capsule, left optic radiation, external capsule, splenium of the corpus callosum, superior longitudinal fasciculus, superior frontal and parietal-occipital nerve fibers.

Charles Bonnet syndrome (CBS) is defined as complex persistent visual hallucinations in the absence of mental disorder. It is associated with advanced age and poor vision. It is common, with prevalence estimates of up to 63% among older people with significant visual impairment. CBS would not be diagnosed in the presence of dementia, but its relationship to milder cognitive impairment is unclear. The few studies that have examined this are underpowered and provide contradictory results. There are 16 case reports of dementia emerging in people with a diagnosis of CBS. These cases raise the possibility of an association between impaired insight at diagnosis of CBS and the subsequent development of dementia. This thesis reports the findings of a prospective cohort study which describes changes in cognitive functioning over one year in patients with CBS and age-matched controls. Participants were recruited from low vision and glaucoma assessment clinics. A clinical assessment was carried out by an old age psychiatrist, and participants had a detailed assessment of visual functioning. This thesis also describes the findings of the first study to use voxel-based morphometry (VBM) to investigate changes in volume of grey and white matter in CBS. Participants were recruited from the same clinics as the cohort study, and underwent MRI scanning on a 1.5T scanner, to a protocol designed to produce 1mm3 voxels. Twelve participants with CBS and ten controls were followed up. Two people in the CBS group developed dementia, while none did in the control group. The CBS group showed a mean change in the score on the Addenbrooke’s cognitive examination (ACE-R) of -3.7 points, compared to a change of +1.4 in the control group. This difference was not statistically significant. The CBS participants performed worse on the verbal fluency item of the ACE-R, a difference which was statistically significant. The VBM analysis was conducted on 11 CBS participants and 11 controls. The CBS group showed an increase in grey matter volume in the right cerebellar hemisphere. This difference retained significance after family-wise error correction, non-stationary correction, and ANCOVA to control for the effects of possible confounders. As far as the author is aware, these are the most methodologically robust studies to date to have investigated cognition and morphological brain changes in CBS. The findings of the cohort study were inconclusive. However, the two cases of dementia in CBS patients add weight to the suspicion that this is a clinically important outcome in the condition, and the finding of abnormalities in frontal lobe testing in participants with CBS fits with a theoretical model of visual hallucination generation. Moreover, this type of research appears to be acceptable to a frail and visually disabled population, and studies powered to investigate this issue more fully would be feasible. The VBM findings report the presence of underlying structural brain abnormalities in CBS, in a region not usually associated with visual hallucinations. Possible links with Lewy body dementia, and implications for theories of visual hallucinations, are discussed.

Attention deficit hyperactivity disorder is one of the most common neurodevelopmental disorders, affecting around 7% of the worldwide population in their everyday life. It has been suggested that individuals with ADHD differ in gray matter volume from typically developing controls. However, findings on in which brain areas these differences are located, as well as how gray matter volume is affected by stimulant medication, remain inconclusive. Therefore, this systematic review aimed to investigate any potential differences in gray matter volume in medication-naïve individuals with ADHD compared to controls, focusing on studies using voxel-based morphometry applied to MRI-imaging data A keyword search in the databases Web of Science, Scopus and Medline EBSCO resulted in 349 studies, of which seven met the inclusion criteria and were included in the review. The results included a total of 169 participants diagnosed with ADHD and 148 typically developing controls. Findings suggested decreased cerebellar gray matter volume, potential gender-wise volume differences in the anterior cingulate cortex, and a decrease in caudate gray matter volume, specifically in adults with ADHD. Some limitations include small sample sizes, possible effects of age on gray matter volume, and the overall heterogeneous nature of the disorder. The present review agrees that individuals with ADHD exhibit differences in gray matter volume, but also highlights the importance of expanding research on medication-naïve subjects, to be able to draw more robust scientific conclusions about the neural correlates of ADHD in the future.