臺灣博碩士論文加值系統

背景與目的: 在1979年台灣發生食用米糠油造成多氯聯苯 (PCBs)中毒事件，受害者稱為「油症」；經胎盤而暴露多氯聯苯的油症第二代從嬰兒時期到青少年時期在神經心理測驗都存在認知功能障礙 。本研究追蹤油症第二代的智力量表，並藉功能性磁振造影(fMRI)觀察中樞系統功能連接和任務時活化的腦網絡，並探討腦網絡活動與認知功能的關聯性。

方法: 對10位油症第二代和12位健康控制組，進行魏氏成人智力量表(WAIS-III)測驗與功能磁振造影，分別利用後扣帶回、左中顳區、左或右前下頂小葉與左下額葉溝為種子點區域，進行靜息態腦功能連接分析；並且觀察「空間工作記憶」任務時皮質的去活化與「視覺空間注意」任務時空間注意力相關腦區的功能偶合。

結果: 油症第二代成年後的魏氏智力分數與控制組沒有差異。油症第二代相較於控制組，工作記憶任務下默認網路的重要節點—內側前額葉(mPFC)—的去活化降低；執行空間注意任務時，左中顳葉運動敏感區域、楔前葉與左前腦島這些負責空間注意力腦區間的功能連接降低。靜息狀態腦功能連接分析顯示油症第二代執行注意網絡和右下頂小葉的功能連接增強；右額頂葉控制網絡與左側顳頂交界、左腦島、右側緣上迴的功能連接減弱；左額頂葉控制網絡與左中額迴功能連接減弱。語言網絡與默認網絡內的功能連接與控制組沒有差異。

結論: 本研究顯示成年油症第二代在臨床上認知功能已正常化，但以功能磁振造影觀察其在任務執行時，默認網絡中內側前額葉(mPFC)的去活化不足，空間注意力相關腦區間功能連接下降，並且靜息狀態表現出的多套腦功能連接網絡異常，可能與多氯聯苯(PCBs)暴露影響神發育有密切的相關性。

Background and aim: In 1979, there were people poisoned by polychlorinated biphenyls (PCBs) due to ingestion of contaminated cooking oil in Taiwan. The victims were called “Yucheng, oil disease”. Yucheng offspring with indirect transplacenta exposure to PCBs were noticed to have cognitive dysfunction by neuropsychological test since childhood to adolescence in previous studies. This study follows up IQ test in Yucheng offspring, analyses the cerebral functional connectivity and task activated brain networks in functional magnetic resonance image (fMRI). We discuss the relationship of brain functional network and neurocognitive function.

Method: 10 Yucheng offspring and 12 health controls undergo Wechsler Adult Intelligence Scale (WAIS) test and brain magnetic resonance image study. We get various brain networks by seed region with posterior cingulate cortex (PCC), left middle temporal motion-sensitive area (MT+), right or left anterior inferior parietal lobule and left inferior frontal sulcus, to analyze the temporal coherence of BOLD signal fluctuation in resting state. Cortical deactivation during working memory task in comparison to control task and functional coupling of spatial attentive areas during spatial attention task are also analyzed.

Results: Comparing adult of Yucheng offspring with health controls, no difference in the WAIS score is observed. In working memory task, there is reduced deactivation of medial prefrontal cortex (mPFC) which is an important node in default mode network (DMN). During spatial attention task, there is reduced functional connectivity between regions associated with processing of spatial attention, such as left anterior insula, left middle temporal area and precuneus. As for functional coupling of brain networks in resting state, Yucheng offspring reveal increased connectivity to right inferior parietal lobule (RIPL) in executive attention network, reduced connectivity to left temporoparietal junction (TPJ), left insula, and right supramarginal gyrus in right frontoparietal control network (FPCN) ,as well as reduced connectivity to left middle frontal gyrus in left FPCN. There is no difference in functional connectivity within DMN and language network among two groups.

Conclusion: We describe normalization of clinical cognitive function in Yucheng offspring in adulthood, while there is failure to deactivate the mPFC within DMN during executive task and aberrant functional connectivity within various brain networks subclinically. These findings may contribute to the understanding of prenatal PCBs exposure and consequence of neural network change in Yucheng offspring.

第一章、緒論 (Introduction) 8
1.1 研究背景 8
1.1.1 油症事件 8
1.1.2 多氯聯苯(PCBs)及同源物對油症二代的神經認知功能與行為影響 9
1.1.3 台灣油症第二代的神經認知與行為功能文獻回顧 9
1.2 靜息態功能性核磁造影功能連接網絡 10
1.2.1 靜息態腦功能連接網絡在認知、精神疾病研究 10
1.2.2 靜息態各種腦功能連接網絡 11
1.2.3 默認網絡 (Default mode network) 12
1.2.4 額頂葉控制網絡(FPCN)、默認網絡(DMN)與執行注意網絡(EAN)之間的關係 14
1.2.5 默認網絡(DMN)去活化(deactivation)在認知與疾病的角色 14
1.2.6 靜息態網路功能連接的分析方法 15
1.3 研究動機與研究問題 16
1.4 研究假說與目標 (1): 油症第二代成人的認知功能追蹤與腦功能連接網絡分析 17
1.5 研究假說與目標 (2): 油症第二代默認網絡(DMN)及工作記憶任務腦區去活化 17
第二章、研究方法與步驟 18
2.1 受試者 (Subjects) 18
2.2 研究方法 18
I. 任務態狀功能磁共振成像— 空間工作記憶測驗 19
II. 靜息態核磁共振檢查方法 20
III. 靜息狀態功能磁共振成像掃描序列 20
IV. 任務態功能磁共振成像掃描序列 20
V. 功能磁振影像(fMRI) 數據分析 21
VI. 靜型態fMRI數據分析 21
2.3 統計分析 22
第三章、 結果 23
3.1 油症第二代成人的認知功能追蹤與腦功能性網絡分析 23
3.1.1 油症第二代成人與控制組的認知功能WAIS-III中文版分數比較 23
3.1.2 油症第二代成人與控制組腦功能網絡分析及比較 23
3.2 油症第二代成人空間工作記憶任務時默認網絡的去活化 26
3.2.1 油症第二代成人工作記憶任務時去活化的腦區 26
3.2.2 靜息態與執行任務時默認網絡(DMN)連接與差異 26
3.2.3油症第二代相較控制組於空間注意任務時默認網絡連接差異 27
3.2.4 靜息態相較於執行空間注意任務時執行注意網絡(EAN)連接與差異 27
3.2.5 油症第二代相較控制組空間注意任務時執行注意網絡(EAN)連接差異 28
第四章、 討論 29
4.1 油症第二代成人的魏氏智力表現 29
4.2 默認網路的功能連接 30
4.3 油症第二代工作記憶任務下默認網路的去活化 30
4.4 任務狀態與靜息狀態的默認網路連接性與差異 31
4.5 執行注意網絡(EAN) 31
4.6 額頂葉控制網絡與語言網絡 33
第五章、結論與展望 33
第六章、參考文獻 34

Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ.(2005) Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry. May 15;57(10):1079-88.

Anticevic, A. et al. (2010) When less is more: TPJ and default network deactivation during encoding predicts working memory performance. Neuroimage 49, 2638–2648

Bai F, Zhang Z, Yu H, et al. (2008) Default-mode network activity distinguishes amnestic type mild cognitive impairment from healthy aging: a combined structural and resting-state
functional MRI study. Neurosci Lett, 2008, 438(1):111-115.

Bluhm RL, Miller J, Lanius RA, et al. (2007) Spontaneous low frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophr Bull, 2007, 33(4):1004-1012.

Castellanos FX, Margulies DS, Kelly AMC, et al.(2008) Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008;63:332–337

Biswal B, Yetkin FZ, Haughton VM, et al. (1995) Functional connectivity in the motor
cortex of resting human brain using echo-planar MRI. Magn Reson Med 1995;34:537– 41

Calhoun VD, Adali T, Pearlson GD, Pekar JJ. (2001)Spatial and temporal independent component analysis of functional MRI data containing a pair of task-related waveforms. Hum Brain Mapp. 2001 May;13(1):43-53.

Cavanna AE, Trimble MR. (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain. 2006 Mar;129(Pt 3):564-83. Review

Chen YCJ, Guo YL, Hsu CC, Rogan WJ (1992) Cognitive development of Yu-Cheng (‘oil-disease’) children prenatally exposed to heat-degraded PCBs. JAMA 268:3213–3218

Chen HL, Lee CC, Liao PC, Guo YL, Chen CH, Su HJ (2003) Associations between dietary intake and serum polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) levels in Taiwanese. Environ Res 91:172–178

Corbetta M, Shulman GL. (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002 Mar;3(3):201-15.

Cordes D, et al. (2000) Mapping functionally related regions of brain with functional connectivity MR imaging. AJNR Am J Neuroradiol. 2000 Oct;21(9):1636-44

Damoiseaux JS, Beckmann CF, Rombouts SA,et al. (2008) Reduced resting-state brain activity in the "default network" in normal aging. Cereb Cortex. 2008 Aug;18(8):1856-64.

Eckert MA, Menon V, Walczak A, Ahlstrom J, Denslow S, Horwitz A, Dubno JR. (2009). At the heart of the ventral attention system: the right anterior insula. Hum Brain Mapp. 30(8):2530-41

Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME.(2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9673-8.

Fornito, A. et al. (2012) Competitive and cooperative dynamics of large-scale brain functional networks supporting recollection. Proc. Natl. Acad. Sci. U.S.A. 109, 12788–12793

Fransson P. (2005) Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum Brain Mapp. 2005 Sep;26(1):15-29.

Guo YL, Lai TJ, Chen SJ, Hsu CC (1995) Gender-related decrease in Raven’s Progressive Matrices scores in children prenatally exposed to polychlorinated biphenyls and related
contaminants. Bull Environ Contam Toxicol 55:8–13

Guo YL, Ryan JJ, Lau BPY, Yu ML, Hsu CC. (1997). Blood serum levels of PCBs and PCDFs in Yucheng women 14 years after exposure to a toxic rice oil. Arch Environ Con Toxicol 33:104–108

Guo YL, Yu ML, Hsu CC, Rogan WJ. (1999) . Chloracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-year follow-up of the Taiwan Yucheng cohort. Environ Health Perspect 107:715–719.

Gazzaley, A. et al. (2008) Age-related top-down suppression deficit in the early stages of cortical visual memory processing. Proc. Natl. Acad. Sci. U.S.A.105, 13122–13126.

Gusnard DA, Raichle ME, Raichle ME. (2001) Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci. 2001 Oct;2(10):685-94. Review.

Greicius MD, Krasnow B, Reiss AL, Menon V. (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.Proc Natl Acad Sci USA. 2003;100(1):253-258.

Greicius MD, Srivastava G, Reiss AL, Menon V. (2004) Default-mode network activity distinguishes Alzheimer''s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42.

Grahn JA, Parkinson JA, Owen AM. (2008) The cognitive functions of the caudate nucleus.Prog Neurobiol. 2008 Nov;86(3):141-55.

Justin L. et al. (2008) Evidence for a Frontoparietal Control System Revealed by Intrinsic Functional Connectivity. J Neurophysiol 100: 3328 –3342.

Hampson M, Driesen N, Roth JK, Gore JC, Constable RT.(2010) Functional connectivity between task-positive and task-negative brain areas and its relation to working memory performance. Magn Reson Imaging. 2010 Oct;28(8):1051-7

Hayden, B.Y. et al. (2009) Electrophysiological correlates of default mode processing in macaque posterior cingulate cortex. Proc. Natl. Acad. Sci. U.S.A. 106, 5948–5953.

Kelly AM, Uddin LQ, Biswal BB, Castellanos FX, Milham MP. (2008) Competition between functional brain networks mediates behavioral variability. Neuroimage. 2008 Jan 1;39(1):527-37.

Koechlin E, Basso G, Pietrini P, Panzer S, Grafman J. (1999) The role of the
anterior prefrontal cortex in human cognition. Nature 399: 148 –151, 1999

Lai TJ, Liu X, Guo YL, Guo NW, Yu ML, Hsu CC, Rogan WJ. (2002) A cohort study of behavioral problems and intelligence in children with high prenatal polychlorinated biphenyl exposure. Arch Gen Psychiatry. 2002 Nov;59(11):1061-6.

Maguire EA. (2001) Neuroimaging studies of autobiographical event memory. Philos Trans R Society Lond B Biol Sci356: 1441–1451, 2001.

LaBar KS, Gitelman DR, Parrish TB, Mesulam M. (1999) Neuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects. Neuroimage. 1999 Dec;10(6):695-704.

McKiernan KA, D''Angelo BR, Kaufman JN, Binder JR. (2006) Interrupting the "stream of consciousness": an fMRI investigation. Neuroimage.2006 Feb 15;29(4):1185-91.

Manoliu A, Riedl V, Zherdin A, et al. (2013) Aberrant Dependence of Default Mode/Central Executive Network Interactions on Anterior Insular Salience Network Activity in Schizophrenia. Schizophr Bull. 2013 Mar 21

Miller EK. (2000) The prefrontal cortex and cognitive control.Nat Rev Neurosci1:
59 – 65, 2000

Muller NG, Knight RT. (2006) The functional neuroanatomy of working memory: contributions of human brain lesion studies. Neuroscience. 2006 Apr 28;139(1):51-8.

Raichle ME, MacLeod AM, Snyder AZ, et al. (2001) A default mode of brain function. Natl Acad Sci USA 2001;98:676– 82.

Raichle, M.E. and Snyder, A.Z. (2007) A default mode of brain function: a brief history of an evolving idea. Neuroimage 37, 1083–1090 discussion 1097–1089.

Safe S (1987) Determination of 2,3,7,8,-TCDD toxic equivalent factors (TEFs): support for the use of the in vitro AHH induction assay. Chemosphere 16:791–80.

Schantz SL, Gasior DM, Polverejan E, McCaffrey RJ, Sweeney AM, Humphrey HEB, et al.( 2001.) Impairment of memory and learning in older adults exposed to polychlorinated biphenyls via consumption of Great Lake fish. Environ Health Perspect 109:605–61.

Seo BW, Powers BE, Widholm JJ, Schantz SL.(2000). Radial arm maze performance in rats following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol. 2000 Jul-Aug;22(4):511-9.

Schantz SL. (1996)Developmental neurotoxicity of PCBs in humans: what do we know　and where do we go from here? Neurotoxicol Teratol. 1996;18:217-227; discussion, 229-276.

Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H Reiss AL, Greicius MD. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 27: 2349–2356, 2007

Seegal RE. (2000) The neurotoxicological consequences of developmental exposure to PCBs.Toxicol Sci. 2000;57:1-3.

Winneke G. (2011). Developmental aspects of environmental neurotoxicology: lessons from lead and polychlorinated biphenyls. J Neurol Sci. 2011 Sep 15;308(1-2):9-15.

Shulman GL, McAvoy MP, Cowan MC, Astafiev SV, Tansy AP, d’Avossa G, Corbetta M. (2003) Quantitative analysis of attention and detection signals during visual search. J Neurophys90: 3384 –3397, 2003.

Sorg C, Riedl V, Muhlau M, et al. (2007) Selective changes of resting-state networks in individuals at risk for Alzheimer''s disease. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18760-5.

Spreng, R.N. et al. (2010) Default network activity, coupled with the frontoparietal control network, supports goal-directed cognition. Neuroimage 53, 303–317.

Spreng, R.N. (2012) The fallacy of a ‘task-negative’ network. Front. Psychol. 3, http://dx.doi.org/10.3389/fpsyg.2012.00145

Steven M. Nelson et a. (2007) Role of the anterior insula in task-level control and focal attention. Brain Struct Funct (2010) 214:669–680

Vincent JL, Snyder AZ, Fox MD, Shannon BJ, Andrews JR, Raichle ME, Buckner RL.(2006) Coherent spontaneous activity identifies a hippocampal-parietal memory network. J Neurophysiol. 2006 Dec;96(6):3517-31.

Wagner AD, Shannon BJ, Kahn I, Buckner RL.(2005) Parietal lobe contributions to episodic memory retrieval. Trends Cogn Sci9: 445– 453, 2005.

Wenderoth N, Debaere F, Sunaert S, Swinnen SP (2005). "The role of anterior cingulate cortex and precuneus in the coordination of motor behaviour". Eur J Neurosci 22 (1): 235–46

Whitfield-Gabrieli, S. et al. (2009) Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 106, 1279–1284.

Widholm JJ, Clarkson GB, Strupp BJ, Crofton KM, Seegal RF, Schantz SL (2001) Spatial reversal learning in Aroclor 1254-exposed rats: sex-specific deficits in associative ability and inhibitory control. Toxicol Appl Pharmacol 174:188–198.

Williamson P.(2007) Are anticorrelated networks in the brain relevant to schizophrenia? Schizophr Bull. 2007 Jul;33(4):994-1003.

Wong CK, Chen CJ, Cheng PC, Chen PH(1982) Mucocutaneous Manifestations of Polychlorinated-Biphenyls (Pcb) Poisoning - a Study of 122 Cases in Taiwan. Brit J Dermatol 1982, 107(3):317-323.

Yu ML, Guo YL, Hsu CC, Rogan WJ. (2000). Menstruation and reproduction in women with polychlorinated biphenyl (PCB) poisoning: long-term follow-up interviews of the women from the Taiwan Yucheng cohort. Int J Epidemiol 29:672–677.

Zhou Y et al.(2008) Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer’s diseaseand mild cognitive impairment Alzheimer’s & Dementia 4 (2008) 265–270.

陳榮華、陳心怡: 魏氏成人智力量表第三版（中文版）指導手冊學社. 中國行為科學社 2002.