휴지상태 대뇌에서 후측 대상 피질의 기능적 특징: 영역 분할 및 경도인지장애와 알츠하이머 병에서의 변화

Abstract

The posterior cingulate cortex (PCC) is highly associated various brains circuits simultaneously and may serve various functions. Moreover, the subdivisions of the PCC have been suggested based on its cytoarchitecture with dorsal and ventral PCC (dPCC and vPCC). However, the functionally subdivisions of the PCC were not always match the anatomical boundaries in human. Parcellation with a various functional properties and clustering algorithms is required step towards understanding functionally organization of regions and anatomy-function association in human brain. In this dissertation, I have a hypothesis that the PCC could functionally parcellate several sub-regions using specific functional information and clustering algorithm. According to the functional connections and clustering algorithms, the predicted sub-regions in the PCC were different. The predicted each sub-regions of the PCC were usually fragmentation regions using the whole brain and diffuse functional connections, whereas there were usually clearly separated PCC using the local functional connections and hierarchical clustering. The results suggest that the PCC has functionally hierarchical regions and the sub-regions of the PCC were more exhibit difference of local connections than difference of whole brain and diffuse connections. In addition, the PCC functionally divided into 2 regions, such as dPCC and vPCC, besides it also divided into four regions resulting in agreement between functional parcellation and anatomical-defined regions. Even though the PCC has several functional sub-regions, recently, seed-based approach in resting state functional magnetic resonance imaging (RS FMRI) which has selection bias was commonly used to analyze default mode network (DMN) in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Moreover, most of DMN studies in patient with aMCI and AD were based only on the comparing two groups, namely patients and controls. Information derived from comparing the three groups, normal, aMCI, and AD group, simultaneously may lead us to better understand the progression of dementia. In this dissertation, the purpose of second study was to investigate patterns of functional alteration in the RS DMN using independent component analysis across the continuum from normal aging to aMCI and AD, and explore whether the differences in functional connectivity are associated with differences in cognitive ability. The results revealed differences throughout the left PCC, left middle temporal gyrus (MTG), right middle frontal gyrus (MFG), and bilateral parahippocampal gyrus (PHG). Both patients with aMCI and AD showed decreased connectivity in the left PCC and left PHG compared with healthy subjects. Furthermore, patient with AD also showed decreased connectivity in the left MTG and right PHG. Increased functional connectivity was observed in the right MFG of patients with AD compared with other groups. Mini-Mental State Examination scores exhibited significant positive and negative correlations with functional connectivity in PCC, MTG and MFG regions. Taken together, an increased functional connectivity in the MFG for AD patients might compensate for the loss of function in the PCC, MTG via compensatory mechanisms in cortico-cortical connections. Moreover, to avoid seed selection bias by the investigators, a multi-method approach using regional homogeneity, amplitude of low-frequency fluctuations, fractional ALFF and global brain connectivity was used to investigate differences between three groups in third study of this dissertation. According to the choice of RS FMRI approach used, the patterns of functional alteration were slightly different. Nevertheless, patients with aMCI and AD displayed consistently decreased functional characteristics with all approaches. All approaches showed that the functional characteristics in the left PHG were decreased in AD patients compared with healthy subjects. Although some regions were slightly different according to the different RS FMRI approaches, patients with aMCI and AD showed a consistent pattern of decreased functional characteristics with all approaches. The various analyses of the PCC in this dissertation could enhance understanding of several functional circuits in the PCC, and avoid seed selection bias by the investigators for diagnosis of patients with aMCI and AD using various RS FMRI approaches.|후측 대상 피질은 뇌의 다양한 회로에 동시에 관련이 있고, 다양한 기능을 한다. 게다가 후측 대상 피질의 하부조직은 세포구조기반으로 2군데로 나눠진다고 알려져 있다. 그러나 후측 대상 피질의 기능적 하부조직은 구조적 경계와 항상 일치하지 않은 결과를 보여주었다. 다양한 기능적 정보를 이용하고 다양한 분할 알고리즘으로 영역 분할을 하는 것은 영역의 기능적 구성과 뇌의 구조와 기능의 관계를 알아보는데 필요한 단계이다. 따라서 본 논문에서는 후측 대상 피질을 여러 가지 기능정보 및 분할 알고리즘으로 기능적인 하부구조로 분할 가능하다는 가설로 진행하였다. 기능적 정보와 분할 알고리즘에 따라, 예측된 후측 대상 피질의 하부구조는 달랐다. 다양한 기능적 정보와 분할 방법을 통해 후측 대상 피질의 구조적 경계와 일치하는 기능적 분할을 시행하였고, 후측 대상 피질의 다양한 기능적 특성을 확인 하였다. 후측 대상 피질은 기존에 알려진 것과 같이 기능적으로 등쪽, 배쪽 2군데로 나눠졌고, 기존 해부학적 위치와 비슷한 총 4군데로 기능적 분할이 가능했다. 후측 대상 피질이 다양한 하부구조를 가졌지만, 최근 휴지상태 기반 기능적 자기공명 영상 연구에서 경도인지장애 및 알츠하이머 병 환자 연구는 표본 선정 편파를 가진 관심 영역 기반 연구를 진행해왔다. 게다가 환자, 정상인 중심의 2군으로 나누어 차이를 보았다. 다음 연구에서는 정상인, 경도인지장애 환자, 알츠하이머 병 환자, 이렇게 3군의 디폴트 모드 네트워크를 독립 성분 분석을 통해 동시에 비교 분석하였다. 3군의 차이는 왼쪽 후측 대상 피질, 왼쪽 중간 측두엽, 오른쪽 중간 전두엽, 그리고 양쪽 해마이랑 쪽에서 나타났다. 환자 모두 왼쪽 후측 대상 피질, 왼쪽 중간 측두엽에서 연결성이 감소하였고, 알츠하이머 병 환자에게선 오른쪽 중간 전두엽에서 기능적 연결성이 증가하였다. 또한 인지기능 점수와도 양의, 음의 상관관계를 보여주었다. 오른쪽 중간 전두엽에서 기능적 연결성이 증가한 것은 아마 후측 대상 피질 및 중간 측두엽에서의 기능적 감소를 보완하기 위한 작용으로 보여졌다. 독립 성분 분석 이외에 표본 선정 편파를 피하기 위한 4가지 휴식상태의 기능적 자기공명 영상 분석 방법으로 경도인지장애 및 알츠하이머 병 환자의 기능적 특징을 분석해보자 하였다. 분석 방법에 따라 결과는 차이가 났지만, 경도인지장애 및 알츠하이머 병 환자에게선 모든 방법 결과가 기능적으로 감소하는 경향을 보여주었다. 특히 왼쪽 해마이랑 쪽에서 알츠하이머 병 환자가 정상인에 비해 기능적으로 감소하는 것을 보여주었다. 이번 논문은 후측 대상 피질의 다양한 기능적 회로를 이해하는데 도움이 될 것이며, 표본 선정 편파를 피하는 다양한 분석을 통해 경도인지장애 및 알츠하이머 병 환자의 진단에 유용하게 쓰일 것으로 기대 된다.; The posterior cingulate cortex (PCC) is highly associated various brains circuits simultaneously and may serve various functions. Moreover, the subdivisions of the PCC have been suggested based on its cytoarchitecture with dorsal and ventral PCC (dPCC and vPCC). However, the functionally subdivisions of the PCC were not always match the anatomical boundaries in human. Parcellation with a various functional properties and clustering algorithms is required step towards understanding functionally organization of regions and anatomy-function association in human brain. In this dissertation, I have a hypothesis that the PCC could functionally parcellate several sub-regions using specific functional information and clustering algorithm. According to the functional connections and clustering algorithms, the predicted sub-regions in the PCC were different. The predicted each sub-regions of the PCC were usually fragmentation regions using the whole brain and diffuse functional connections, whereas there were usually clearly separated PCC using the local functional connections and hierarchical clustering. The results suggest that the PCC has functionally hierarchical regions and the sub-regions of the PCC were more exhibit difference of local connections than difference of whole brain and diffuse connections. In addition, the PCC functionally divided into 2 regions, such as dPCC and vPCC, besides it also divided into four regions resulting in agreement between functional parcellation and anatomical-defined regions. Even though the PCC has several functional sub-regions, recently, seed-based approach in resting state functional magnetic resonance imaging (RS FMRI) which has selection bias was commonly used to analyze default mode network (DMN) in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Moreover, most of DMN studies in patient with aMCI and AD were based only on the comparing two groups, namely patients and controls. Information derived from comparing the three groups, normal, aMCI, and AD group, simultaneously may lead us to better understand the progression of dementia. In this dissertation, the purpose of second study was to investigate patterns of functional alteration in the RS DMN using independent component analysis across the continuum from normal aging to aMCI and AD, and explore whether the differences in functional connectivity are associated with differences in cognitive ability. The results revealed differences throughout the left PCC, left middle temporal gyrus (MTG), right middle frontal gyrus (MFG), and bilateral parahippocampal gyrus (PHG). Both patients with aMCI and AD showed decreased connectivity in the left PCC and left PHG compared with healthy subjects. Furthermore, patient with AD also showed decreased connectivity in the left MTG and right PHG. Increased functional connectivity was observed in the right MFG of patients with AD compared with other groups. Mini-Mental State Examination scores exhibited significant positive and negative correlations with functional connectivity in PCC, MTG and MFG regions. Taken together, an increased functional connectivity in the MFG for AD patients might compensate for the loss of function in the PCC, MTG via compensatory mechanisms in cortico-cortical connections. Moreover, to avoid seed selection bias by the investigators, a multi-method approach using regional homogeneity, amplitude of low-frequency fluctuations, fractional ALFF and global brain connectivity was used to investigate differences between three groups in third study of this dissertation. According to the choice of RS FMRI approach used, the patterns of functional alteration were slightly different. Nevertheless, patients with aMCI and AD displayed consistently decreased functional characteristics with all approaches. All approaches showed that the functional characteristics in the left PHG were decreased in AD patients compared with healthy subjects. Although some regions were slightly different according to the different RS FMRI approaches, patients with aMCI and AD showed a consistent pattern of decreased functional characteristics with all approaches. The various analyses of the PCC in this dissertation could enhance understanding of several functional circuits in the PCC, and avoid seed selection bias by the investigators for diagnosis of patients with aMCI and AD using various RS FMRI approaches.