注意力不足過動症之神經生物學與基因學研究

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(1)୯ҥᆵ᡼εᏢᙴᏢଣ ᖏ‫׉‬ᙴᏢࣴ‫܌ز‬ റγፕЎ Graduate Institute of Clinical Medicine College of Medicine, National Taiwan University, Doctoral Dissertation. ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱϐઓ࿶ғ‫ނ‬Ꮲᆶ୷ӢᏢࣴ‫ز‬ Neurobiological and Genetic Studies on Attention Deficit Hyperactivity Disorder. ࣴ‫ز‬ғǺ୘‫ד‬႘ Chi-Yung Shang. ࡰᏤ௲௤Ǻଯల޹ റγ ླྀ଻ര റγ Advisor: Susan Shur-Fen Gau, M.D., Ph.D. Wei-Shiung Yang, M.D., Ph.D.. ύ๮҇୯΋ԭ႟Βԃ΋Д January, 2013.

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(4) ᇞᖴ ӣ२೭ϖԃӭ‫ޑ‬റγ੤ᐕำǴӧଯల޹௲௤‫ࡰޑ‬ᏤϐΠǴ‫ך‬வ΋ঁᏢೌࣴ‫ز‬ ‫ߐޑ‬ѦᅇǴ‫ډ‬ԋࣁ΋ঁઓ࿶ғ‫ޑزࣴނ‬Ꮲಞ‫ޣ‬Ǵ೭ύ໔ाགᖴϼӭ‫ޑ‬ΓǴ‫ځ‬ύ२ Ӄाགᖴ‫ޑ‬྽ฅࢂ‫ޑך‬ৱৣଯల޹௲௤ǴӴᕴࢂஒᏢғॺ‫ޑ‬ሡा‫ܫ‬ӧಃ΋ᓬӃǴ ଯ௲௤ߚதԖऐЈӦ௲Ꮴ‫ך‬ӧࣴ‫ز‬ሦୱ΢‫ޑ‬ᏢಞǴ੝ձࢂӧઓ࿶ғ‫ނ‬Ꮲǵᛰ‫ނ‬ ᏢǵаϷ୷Ӣᒪ໺Ꮲ฻Бय़Ǵ‫ך‬வଯ௲௤‫ޑ‬஥ሦ΢ᕇளᜤа‫ق‬േ‫ޑ‬ᔅշǶӕਔଯ ௲௤Ψа‫ي‬բ߾Ǵӧவ٣Ꮲೌࣴ‫ز‬ᆶྣ៝ৎ৥ғࢲ‫ٿ‬Бय़೿ԋࣁ‫ޑॺך‬ന٫ኳ ጄǶќѦΨाགᖴླྀ଻ര௲௤ǵමЎኾ௲௤ǵഋࣁ୲௲௤ǵഋ჏౺௲௤ǵߋ᜽੧ ௲௤ǵаϷᙔӃϡ௲௤ӧറγፕЎ΢๏Ꮲғ‫ޑ‬ᝊ຦ཀ‫ـ‬Ǵᡣ‫ך‬ჹ‫ݙܭ‬ཀΚό‫ى‬ၸ ୏ੱ‫زࣴޑ‬ԖΑ‫׳‬ቶᗡᆶֹ᏾‫ޑ‬ຎഁǴ҂ٰΨය೚Ծρஒറγ੤‫ޑ‬౥཰྽բ΋ঁ ଆᗺǴჹ‫ݙܭ‬ཀΚό‫ى‬ၸ୏ੱ‫ੰޑ‬౛ғ౛ᏢᐒᙯૈԖ‫׳‬ుΕ‫ޑ‬௖૸Ƕ ӕਔΨाགᖴ‫ۀޑך‬ηࢶฑǴӧ‫܌زࣴך‬᠐ਜ‫ޑ‬೭൳ԃය໔ǴӴՔᒿ‫ך‬ཚ‫ډ‬ ໦݅ՐΑ‫ٿ‬ԃǴΞՔᒿ‫ך‬ӣ‫ډ‬ѠчǴ٠Ъӧৎྣ៝‫࠸ঁٿ‬ηǴᓨᓨӦЍ࡭‫ޑך‬π բ‫ک‬Ꮲ཰ǴऩࢂؒԖӴ‫ޑ‬΋ၡ࣬ՔǴ‫੿ך‬ό‫ޕ‬ၰ၀ӵՖय़ჹғ‫ڮ‬ύ΋ԛΞ΋ԛ‫ޑ‬ ࡷᏯǴԖΓᇥ྽΋ঁ‫ۀ‬η‫҆ک‬ᒃǴᜤࡋ࣬྽‫ܭ‬ाᕇளΜঁറγᏢՏǴӧࢶฑ‫ي‬΢ ‫ֹך‬ӄёаӕཀ೭ѡ၉ǴӢࣁԖΑӴǴ‫ޑך‬Ꮲೌࣴ‫ز‬аϷΓғωᡂ‫ֹޑ‬᏾ԶԖཀ ကǶќѦΨाགᖴ‫࠸ޑך‬ηλᝊᆶ౛౛ǴӧдॺΓғԋߏ‫ޑ‬ന໒‫ۈ‬ਔ໔Ǵᡣ‫ך‬ё аୖᆶ٠ϩ٦дॺԋߏ‫ޑ‬഻৹Ǵ೭‫࠸ঁٿ‬ηࢂ΢ࡆ๏‫ॺך‬ৎനᝊ຦‫ޑ‬ᘶ‫کނ‬ౢ ཰ǴΨࢂ‫ך‬΋ғന‫ޕ‬Ј‫϶ܻޑ‬Ǵ྽‫ך‬ӧπբ΢ၶ‫ډ‬਋‫ޑש‬ਔংǴдॺᕴࢂҔനྕ ཪ‫ޑ‬Ᏹ‫ٰܤ‬Ⴔᆸ‫ޑך‬ЈǶ നࡕ‫׳‬ाགᖴओᑋ୷࿎Ǵ᭘ӧ‫يך‬΢Ԗኧόᅰ‫ޑ‬ৱ‫ڂ‬ǴӢࣁ᭘ᡣനӳ‫ޑ‬Դৣ ٰ௲Ꮴ‫ך‬Ǵ፥๏‫ך‬ऍӳ‫ޑ‬ৎ৥ғࢲǴ٠ᡣ‫ߞـ࣮ך‬һғࢲᆶࣽᏢࣴ‫ࢂز‬ёаӕਔ ٠຾‫ޑ‬Ƕᗨฅറγ੤౥཰ΑǴՠ൩Ⴝ٬২ߥᛥӧගነϼࡕਜಃ΋കಃΜΒ࿯‫܌‬ᇥ ‫ޑ‬Ǵ ȨӢࣁ‫ޕ‬ၰ‫ࢂޑߞ܌ך‬ፔǴΨుߞдૈߥӄ‫܌ך‬Ҭбд‫ޑ‬Ǵ‫ٗډޔ‬Вȩ Ǵ‫࣬ך‬ ߞ΢ࡆᗋԖ‫׳‬ऍӳ‫ޑ‬ৱ‫ڂ‬ᆶ٬‫ڮ‬ा‫ך‬ѐֹԋǴӕਔΨ཮ߥӺ‫܌ך‬Ҭૼ‫ޑ‬΋ϪǴӢ.

(5) ࣁ᭘όՠ፥ᅽ๏᭘‫ٽޑ‬ζॺǴ‫ࢂ׳‬ᡣ᭘‫ٽޑ‬ζॺԋࣁձΓ‫ޑ‬ઔᅽǼ.

(6) Ҟᒵ ύЎᄔा.....................................................................................................................1 मЎᄔा.....................................................................................................................3 1. ᆣፕ........................................................................................................................5 1.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ᖏ‫ރੱ׉‬ǵບᘐǵᆶࢬՉੰᏢࣴ‫ز‬.........................5 1.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ.....................................................8 1.2.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ...............................................................................8 1.2.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ...............................................................................9 1.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ................................................11 1.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ....................................13 1.5 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ................................................................15 1.5.1 DAT1 ୷Ӣᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫࣬ޑ‬ᜢ‫زࣴ܄‬................................15 1.5.2 DAT1 ୷Ӣᆶ୺Չфૈምᛖϐ࣬ᜢ‫܄‬................................................18 1.6 ࣴ‫ز‬ୢᚒᆶଷᇥ............................................................................................20 1.6.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖ...................................................20 1.6.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ.......................................22 1.6.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ...........................23 1.6.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ.......................................................24 2. ࣴ‫ز‬Б‫ݤ‬ᆶ‫׷‬਑...................................................................................................26 2.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ....................................................26 2.1.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ..............................................................................26 2.1.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ..............................................................................28 2.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ................................................31 2.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ....................................32 2.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ................................................................35 2.4.1 DAT1 ୷Ӣᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫࣬ޑ‬ᜢ‫زࣴ܄‬................................35 2.4.2 DAT1 ୷Ӣᆶ୺Չфૈምᛖϐ࣬ᜢ‫܄‬................................................36 3. ่݀.......................................................................................................................39 3.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ....................................................39 3.1.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ..............................................................................39 3.1.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ..............................................................................40 3.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ............................................41 3.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ....................................43 3.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ................................................................43 3.4.1 DAT1 ୷Ӣᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫࣬ޑ‬ᜢ‫زࣴ܄‬................................43.

(7) 3.4.2 DAT1 ୷Ӣᆶ୺Չфૈምᛖϐ࣬ᜢ‫܄‬................................................44 4. ૸ፕ.......................................................................................................................46 4.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ....................................................48 4.1.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ..............................................................................48 4.1.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ..............................................................................50 4.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ................................................56 4.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ....................................60 4.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ................................................................65 4.4.1 DAT1 ୷Ӣᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫࣬ޑ‬ᜢ‫زࣴ܄‬................................65 4.4.2 DAT1 ୷Ӣᆶ୺Չфૈምᛖϐ࣬ᜢ‫܄‬................................................67 5. ৖ఈ.......................................................................................................................70 5.1 ᛰ‫୷ނ‬ӢᏢ...................................................................................................70 5.2 ่ᄬ‫܄‬ᆶфૈ‫܄‬ઓ࿶ቹႽᏢ.......................................................................73 5.3 ቹႽ୷ӢᏢ...................................................................................................75 5.4 ୏‫ނ‬ኳԄ.......................................................................................................78 6. ፕЎमЎᙁॊ.......................................................................................................80 6.1 Neuropsychological dysfunction in ADHD...................................................80 6.1.1 Neuropsychological dysfunction..........................................................80 6.1.2 Neuropsychological endophenotypes...................................................85 6.2 Neuropsychological endophenotypes and atomoxetine in ADHD................92 6.3 Neuroimaging in ADHD................................................................................99 6.4 Genetic association studies on ADHD.........................................................105 6.4.1 Association of DAT1 gene and ADHD................................................105 6.4.2 Association of DAT1 gene and executive dysfunction in ADHD.......111 7. ୖԵЎ᝘.............................................................................................................119 8. ߄ᆶკ.................................................................................................................160 9. ߕᒵ.....................................................................................................................193 9.1 অ཰ය໔ว߄ϐЬाፕЎ..........................................................................193 9.2 অ཰ය໔ว߄ϐ‫ځ‬дፕЎ..........................................................................193.

(8) ύЎᄔा ᜢᗖຒǺ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱǴቆᐏઓ࿶Ј౛ෳᡍǴ୺ՉфૈǴຎ᝺૶ᏫǴᚐယદ ‫ރ‬ᡏઓ࿶ၡ৩Ǵᘉණᓎ᛼೷ቹǴӭЃữᙯၮ୷ӢǴൂ঺ᡏǴೱᙹόѳᑽ. ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱதӝ‫୺ٳ‬ՉфૈምᛖǴՠ‫ځ‬дᇡ‫ޕ‬фૈምᛖ߾ၨϿ೏ࣴ ‫ز‬ǴќѦΨؒԖࣴ‫ز‬᛾ჴ atomoxetine ᛰ‫ݯނ‬ᕍёа‫ׯ‬๓೭٤ᇡ‫ޕ‬фૈምᛖǴԶ ೭٤ᇡ‫ޕ‬фૈምᛖወӧ‫ޑ‬ઓ࿶ᄬ೷ᆶ୷ӢੰӢϝ҂Ԗ‫ۓ‬ፕǶҁറγፕЎஒϩԋа ΠѤঁቫय़ٰӣเ΢ॊୢᚒǶ Ȑ΋ȑઓ࿶Ј౛ᏢБय़Ǻ(a) ௖઩ 53 Տӧ‫ูٽ‬ය೏ບᘐࣁ ADHD ‫ߙޑ‬Ͽԃ Ϸ 53 Տଛჹ‫଼ޑ‬நჹྣಔ‫୺ޑ‬ՉфૈǴаቆᐏઓ࿶Ј౛ෳᡍ (Cambridge Neuropsychological Test Automated BatteryΔCANTAB) ෳໆ‫୺ځ‬ՉфૈǴ่݀ว ౜ ADHD ஻‫ޣ‬ӧ೭Ѥঁ୺Չфૈෳᡍ߄౜֡ၨჹྣಔৡǴ᛾ჴ ADHD ߙϿԃ஻ ‫ޣ‬Ԗᡉ๱‫୺ޑ‬ՉфૈምᛖǴ٠ӧय़ჹፄᚇբ཰ਔሡाᚐѦ‫ڐ‬շǶ (b) а 279 Տ ADHD ஻‫ޣ‬ǵ‫ځ‬҂วੰЋ‫( ى‬n=108)ǵϷ 173 Տ଼நჹྣಔǴ ௖઩‫୺ځ‬Չфૈᆶຎ᝺૶Ꮻࢂցёаԋࣁઓ࿶Ј౛Ꮲ‫ޑ‬ϣ߄౜ࠠǶ‫ॺך‬٬Ҕ CANTAB ٰෳໆ୺ՉфૈаϷຎ᝺૶ᏫǴ่݀ว౜ ADHD ஻‫ځکޣ‬҂วੰЋ‫ى‬ ӧѤঁ୺ՉфૈᆶѤঁຎ᝺૶Ꮻෳᡍ߄౜ၨ଼நჹྣಔৡǴ҂วੰЋ‫ى‬ӧ‫ঁٿ‬ຎ ᝺૶Ꮻෳᡍ‫߄ޑ‬౜ϟ‫ ܭ‬ADHD ‫ک‬ჹྣಔϐ໔Ǵ᛾ჴ୺Չфૈ‫ک‬ຎ᝺૶Ꮻዴჴё բࣁ ADHD ‫ޑ‬ઓ࿶Ј౛Ꮲϣ߄౜ࠠǶ ȐΒȑᛰ‫ނ‬ᏢБय़Ǻа 30 Տ 8 ‫ ډ‬16 ྃ҂මܺҔၸᛰ‫ ޑނ‬ADHD ஻‫ޣ‬Ǵ຾ Չ΋໨࡭ុ 12 ຼ໒‫ܫ‬኱ᠸ‫ ޑ‬atomoxetine ᛰ‫ނ‬၂ᡍǴаᕕှ‫୺ځ‬ՉфૈϷຎ᝺૶ ᏫӧҔᛰࡕ 4 ຼ‫ ک‬12 ຼ‫ׯޑ‬๓Ǵ่݀ว౜஻‫ޣ‬ӧܺᛰࡕନΑᖏ‫߄׉‬౜Ϸ‫཮ޗ‬ф ૈԖᡉ๱຾‫؁‬Ǵӧ‫܌‬ෳ၂‫ޑ‬Ѥ໨୺Չфૈ‫ٿک‬໨ຎ᝺૶Ꮻ߄౜֡Ԗܴᡉ຾‫؁‬Ǵᡉ Ң atomoxetine ёԖਏ‫ׯ‬๓ ADHD ஻‫୺ޑޣ‬Չфૈᆶຎ᝺૶ᏫምᛖǶ ȐΟȑઓ࿶ቹႽᏢБय़Ǻа 25 Տ ADHD ஻ูϷ 25 Տӧԃសǵ‫܄‬ձǵᄍҔ 1.

(9) ЋǵаϷඵ୘ଛჹ‫଼ޑ‬நჹྣಔǴᕕှᚐယદ‫ރ‬ᡏઓ࿶‫ֹޑ״‬᏾‫܄‬аϷ‫୺کځ‬Չ фૈ‫࣬ޑ‬ᜢ‫܄‬Ƕ่݀ว౜஻‫ޣ‬аᘉණᓎ᛼೷ቹ (diffusion spectrum imagingǴDSI) ख़ࡌ‫ୁٿޑ‬ӚѤచᚐယદ‫ރ‬ᡏઓ࿶ၡ৩ (ङѦୁǵϣୁǵ౳ᆂ߻ᚐယǵϷဎѦୁ) ‫ޑ‬΋૓‫܄‬ϐ೽ϩ౦ӛ‫( ܄‬generalized fractional anisotropy) ॶ֡ၨჹྣಔեǴЪ‫ک‬ ADHD ‫ރੱޑ‬ᝄख़ࡋ‫୺ک‬ՉфૈምᛖԖᡉ๱࣬ᜢǴ੝ձࢂѰୁ‫ޑ‬౳ᆂ߻ᚐယ‫ک‬ ဎѦୁ฻ઓ࿶ᠼᆢ‫״‬Ƕ ȐѤȑ୷Ӣᜢᖄ‫܄‬Бय़Ǻ (a) а 273 Տ ADHD ৎ௼ (n=906) ‫ ޑ‬DNA ӧ DAT1 ୷Ӣ΢‫פ‬р 14 ঁൂਡ㧿ለӭࠠ‫( ܄‬SNP) ᆶ 3´variable number of tandem repeat (VNTR)Ǵ่݀೭ 15 ঁ୷Ӣ኱૶‫ ޑ‬LD ่ᄬǴх֖ 3 ঁൂ঺ᡏ୔໔Ǵಃ΋ঁ୔໔ ελࣁ 19kbǴՏ‫ܭ‬ಃΒǵѤǵϤঁϣᡉηǴಃΒঁ୔໔ελࣁ 3kbǴՏ‫ܭ‬ಃΖǵ Μ΋ঁϣᡉηǴಃΟঁ୔໔ελࣁ 953bpǴՏ‫ ܭ‬3´UTRǶൂ঺ᡏϩ‫݋‬ว౜ rs27048 (C) /rs429699 (T) ᆶ‫ݙ‬ཀΚό‫ى‬٥ࠠԖᡉ๱࣬ᜢǴӧໆ‫܄‬ϩ‫݋‬΢Ψว౜ rs27048 (C) /rs429699 (T) ᆶ‫ݙ‬ཀΚό‫ޑރੱى‬ᝄख़ࡋԖᡉ๱࣬ᜢǴᡉҢ DAT1 ୷Ӣӧ ADHD ‫ݙޑ‬ཀΚό‫ى‬٥ࠠ‫ੰޑ‬౛ғ౛ᐒᙯ΢‫ת‬ᄽख़ा‫ف‬ՅǶ (b) DAT1 ୷Ӣᆶ୺Չфૈ‫ޑ‬ᜢᖄ‫܄‬Ǻа 382 Տ ADHD ৎ௼ (n=1298) ‫ޑ‬ DNA ኬҁϷ‫୺ځ‬Չфૈ຾Չϩ‫݋‬Ƕൂ঺ᡏϩ‫݋‬ว౜Ǵಃ΋ঁൂ঺ᡏ୔໔ rs403636 (G) /rs463379 (C) /rs393795 (C) /rs37020 (G) ‫ޜک‬໔πբ૶Ꮻ‫ޑ‬ᒱᇤໆԖᡉ๱࣬ ᜢ‫܄‬ǶᡉҢ DAT1 ୷Ӣӧ ADHD ‫ޜޑ‬໔πբ૶Ꮻምᛖ‫ת‬ᄽख़ा‫ف‬ՅǶ ᆕӝа΢ࣴ‫ز‬Ǵҁറγࣴ‫ز‬ว౜ ADHD ନΑԖ୺Չфૈ‫ޑ‬ምᛖϐѦǴӕਔ ࢂШࣚ΢ಃ΋ঁࣴ‫ز‬᛾ჴຎ᝺૶Ꮻࢂϣ߄౜ࠠǴ٠Ъ atomoxetine ‫ݯ‬ᕍёа‫ׯ‬๓ ୺Չфૈᆶຎ᝺૶ᏫምᛖǴԶ ADHD ‫୺ޑ‬Չфૈምᛖᆶᚐယદ‫ރ‬ᡏઓ࿶ᖄ่Ϸ DAT1 ୷Ӣᡂ౦Ԗܴᡉ࣬ᜢ‫܄‬Ǵ҂ٰሡाᙖҗᛰ‫୷ނ‬ӢᏢаϷቹႽ୷ӢᏢ‫زࣴޑ‬ аࡌҥ ADHD ‫ੰޑ‬౛ғ౛ᐒᙯǶ. 2.

(10) मЎᄔा Keywords and Abbreviations: Attention-deficit/hyperactivity disorder (ADHD), frontostriatal tracts (FS), diffusion spectrum imaging (DSI), executive function (EF), visual memory (VM), Cambridge Neuropsychological Test Automated Battery (CANTAB), DAT1, haplotype, linkage disequilibrium (LD). Although ADHD is often associated with executive deficits, little research has report other cognitive dysfunction in ADHD. No study has investigated the effect of atomoxetine on the cognitive dysfunction in children with ADHD. In addition, the neural correlates and genetic variants of cognitive dysfunction is still inconclusive. The doctoral thesis will answer these questions from four approaches. (1) Neuropsychological approach: (a) Using 53 adolescents with childhood diagnosis of ADHD, and 53 matched controls, we examined their EF assessed by using the tasks involving the EF of the CANTAB. The ADHD group performed worse in all the EF tasks, and needed extra assistance while complex tasks were assigned. (b) Using 279 adolescents with ADHD, 108 unaffected siblings and 173 controls, we examined their EF and VM to test whether EF and VM can be potential endophenotypes for ADHD. The ADHD probands and the unaffected siblings significantly performed worse in all the EF tasks. The unaffected siblings occupied an intermediate position between ADHD probands and controls in the performance on two VM tasks, suggesting that EF and VM can be useful endophenotypes for ADHD. (2) Pharmacological approach: we examined the effect of atomoxetine on EF and VM in 30 drug-naïve boys with ADHD, aged 8-16, in an open-label trial after 12-week treatment. In addition to improvement in clinical and social functions, results showed significant improvement in EF and VM after treatment with atomoxetine for 4 3.

(11) weeks or 12 weeks. Our findings suggest that atomoxetine is effective in improving EF and VM among boys with ADHD. (3) Neuroimaging approach: using 25 children with ADHD and 25 matched controls, we examined the association between the integrity of FS tracts and EF. The FS reconstructed by DSI tractography were subdivided into four segments, including dorsolateral, medial prefrontal, orbitofrontal, and ventrolateral tracts. Children with ADHD had lower generalized fractional anisotropy of all the bilateral frontostriatal fiber tracts. ADHD symptom severity and EF performance significantly correlated with integrity of the FS, particularly the left orbitofrontal and ventrolateral tracts. (5) Genetic association approach: (a) we recruited a Chinese family-based sample (n = 906), and screened 15 polymorphisms across the DAT1 gene, including 14 SNPs and the variable number of tandem repeat (VNTR) polymorphism in 3´-untranslated region (3´UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs). Haplotype analysis showed that a haplotype rs27048 (C) /rs429699 (T) was significantly associated with the inattentive subtype. Our findings indicate that the DAT1 gene may primarily affect the inattentive subtype of ADHD. (b) We extended the family-based sample (n = 1298) and examined the association between DAT1 and EF. Haplotype-based association tests showed that a haplotype rs403636 (G) /rs463379 (C) /rs393795 (C) /rs37020 (G) in HB1 was significantly associated with SWM errors. Our findings indicate that DAT1 plays a role in the SWM errors of ADHD. In summary, in addition to EF, we identified VM as potential endophenotype for ADHD and found significant effects of atomoxetine on EF and VM. We demonstrated that EF was linked to disturbed integrity of frontostriatal tracts and variations of the DAT1 gene. Further pharmacogenetic and imaging genetic studies are needed to establish the pathophysiological pathways underlying ADHD. 4.

(12) 1. ᆣፕ (Introduction). ߻‫ق‬ ӧ‫ߙูٽ‬Ͽԃ‫ޑ‬ᆒઓ੯ੰύǴၸ୏ੱࢂ΋ঁத‫ޑـ‬ᖏ‫׉‬ୢᚒǶȨၸ୏ੱȩ‫ޑ‬ ӄӜࣁȨ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱȩȐAttention-Deficit/Hyperactivity DisorderǴᙁᆀ ADHDȑǶADHD ჹঁΓ‫ޑ‬Ꮲ཰ǵπբϷΓሞᜢ߯ǵৎ৥‫ޑ‬ᓸΚ‫཮ޗک‬࿶ᔮ‫ޑ‬ፂ ᔐཱུεǶ೷ԋ ADHD ‫ޑ‬চӢҞ߻ᗨฅؒԖ‫ۓ‬ፕǴՠࢂ୷ҁ΢ࣴ‫ز‬ว౜Ьा‫ޑ‬ୢ ᚒࢂٰԾ୷Ӣᒪ໺‫ޑ‬ᡂ౦Ǵ೷ԋ࠸ηԖό஑Јǵၸ୏ǵᆶፂ୏฻ੱ‫ރ‬ǶќѦӧઓ ࿶ғ‫ނ‬ᏢБय़཮Ԗઓ࿶Ј౛Ꮲᆶઓ࿶ቹႽᏢБय़‫ޑ‬౦தǶҁЎஒଞჹ ADHD ᖏ ‫ރੱ׉‬ᆶບᘐǵࢬՉੰᏢࣴ‫ز‬ǵ୷Ӣᒪ໺Ꮲǵઓ࿶Ј౛Ꮲǵઓ࿶ቹႽᏢǵаϷᛰ ‫ݯނ‬ᕍ฻ቫय़уа௖૸Ƕ. 1.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ᖏ‫ރੱ׉‬ǵບᘐǵᆶࢬՉੰᏢࣴ‫ز‬ ADHD ‫ޑ‬ЬाਡЈੱ‫ࢂރ‬ό஑Јǵၸ୏‫ک‬ፂ୏Ƕό஑ЈБय़Ǵхࡴ: ؒԖ‫ݙ‬ ཀ‫ډ‬ಒ࿯ǵಉЈεཀǵค‫ݙុ࡭ݤ‬ཀΚ‫ܭ‬ၨ࢏ᔿख़ᙟ‫ޑ‬ϣ৒ǵ‫ݙ‬ཀΚϩණǵձΓ ჹдᖱ၉ਔЈόӧోǵؒऐЈ᠋ֹࡰҢ‫ڦ֊܈‬ǵሡाόଶӦගᒬВதғࢲ‫ޑ‬٣ ௃ǵ‫׋‬ҧதҔ‫ܿޑ‬ՋǵؒԖਔ໔ᢀ‫ۺ‬Ƕၸ୏Бय़Ǵхࡴ: າٰາѐǵ‫ݽ‬ଯ‫ݽ‬եǵ ό‫܂‬ӒᓀǵᆒΚ‫ܮ‬౰ǵό᝺ளಕǵ֤όՐࣗԿ‫ܭ‬ᚆ໒Տηǵ֤ਔ‫ي‬ᡏ‫סٰס‬ѐǵ ୏ٰ୏ѐ‫׋ވ܈‬ЋࡰǶ೭٤࠸η཮୏բКၨಉᎹǴၮ୏‫ڐ‬ፓό٫Ǵத཮Ԗཀคཀ Ӧ࿘᝻ձΓǴަᡏ୏բ᡿ӭ‫ޑ‬Ǵ৒ܰཅΓჇ‫܈‬೏ᇤ཮ѺΓǶЪдॺёૈ཮Кၨང ᖱ၉Ǵ‫ٯ‬ӵӧό፾ӝ‫ޑ‬௃‫ݩ‬ΠǴӧӞ໭ਔ‫܈‬ᔈ၀Ӽᓉ‫ޑ‬௃ნΠǴς࿶೏ගᒬΑό ၀ᖱ၉Ǵёૈ‫ה‬όՐǴ൳ϩដϐࡕΞ໒‫ۈ‬ᝩុᖱ၉Ǵᜤа௓‫ڋ‬όᖱ၉Ƕፂ୏Бय़Ǵ хࡴ: ؒԖऐЈǵόᆅձΓӭԆ‫܈‬ձΓӧፋ၉Ǵд཮ѺᘐΓৎ‫ࢂ܈‬ක቏ǹձΓჹ дᇥ၉ਔдΨ཮ؒԖऐЈ᠋ձΓᖱֹǴ཮ௗ၉‫࡚܈‬๱ӣเǹჹ‫ࡐܭ‬ӭ٣௃ёૈ཮ ӳᆅ໕٣ǵ዗ЈၸࡋǴத཮ඹձΓрཀ‫ـ‬Ǵ྽ձΓό᠋д‫ޑ‬ཀ‫ـ‬ਔ൩཮ౢғፂँ 5.

(13) ‫܈‬όඍ‫ז‬ǹ࣬ჹӦǴдΨКၨ৒ܰؒԖऐЈǴόᜫཀ௨໗ວܿՋ‫ވ܈‬ǴКၨᜤᆶ дΓ፺ࢬǴջ٬όளό௨໗ǴдΨ཮߄౜рКၨόऐྠ‫܈‬όଯᑫ‫ޑ‬ኬηǶ᏾ᡏٰ ᖱǴ೭٤࠸ηӢࣁ‫ځ‬੝ቻ཮೷ԋ‫ځ‬Ꮲ཰߄౜όӵ‫ځ‬၀Ԗ‫ૈޑ‬ΚǴЪԖܴᡉΓሞ΢ ‫ޑ‬ୢᚒǴόᆅӧӕᏆБय़‫ࢂ܈‬ᆶР҆ǵԴৣǶӧՉࣁ΢ёૈ཮Ԗ΋٤όᒥӺೕ‫ۓ‬ǵ ፂ୏‫܈‬υᘋձΓ‫ޑ‬Չࣁ (Fischer et al., 1990)Ƕ Ҟ߻ບᘐ‫ٿޑ‬ε‫س‬಍ࢂ ICD-10 Ȑ୯ሞ੯ੰϩᜪಃ 10 ‫ހ‬ȑ Ǵࢂ୯ሞፁғಔᙃ ‫ހޑ‬ҁȐHyperkinetic Disorderȑ Ǵќ΋ঁ߾ࢂऍ୯‫ ޑ‬DSM-IV Ȑ‫ݙ‬ཀΚό‫ى‬ၸ୏ ੱǴAttention-Deficit/Hyperactivity DisorderǴAD/HDǴAPA 1994ȑǶ୷ҁ΢೭‫ٿ‬ ε‫س‬಍‫఼܌‬ᇂ‫ޑ‬Չࣁ੝ቻεठ΢ࢂ࣬ӕ‫ޑ‬ǴЬा‫ޑ‬ৡ౦ࢂӧԖคບᘐ٥ࠠǶ DSM-IV Ԗၨቨቶ‫ۓޑ‬ကǴӧΐ໨ό஑Ј‫ރੱޑ‬ύाԖϤ໨Ǵၸ୏ᆶፂ୏‫ޑ‬ΐ໨ ύाԖϤ໨ω಄ӝບᘐǴӕਔ಄ӝ೭‫ٿ‬εੱ‫ރ‬ဂǴω಄ӝషӝ٥ࠠ ȐCombined TypeȑǴऩੱ‫ރ‬ኧѝԖ಄ӝό஑Ј‫܈‬ၸ୏/ፂ୏ੱ‫ރ‬ဂϐ΋Ǵ߾ࣁό஑Ј٥ࠠ ȐInattentive Typeȑ‫܈‬ၸ୏/ፂ୏٥ࠠ ȐHyperactive-Impulsive TypeȑǶICD ߾ࢂ ௦‫ڗ‬ၨ੟႕‫ۓޑ‬ကǴ‫ݙ‬ཀΚǵၸ୏‫ک‬ፂ୏Οᅿੱ‫ރ‬ဂाӕਔр౜ω಄ӝǴ٠Ъஒ ၉ӭ‫ܫ‬ӧፂ୏‫ޑ‬೽ϩǴӢԜӧΐ໨ό஑Јੱ‫ރ‬ύाԖϤ໨Ǵϖ໨ၸ୏ੱ‫ރ‬ा಄ӝ Ο໨ǴѤ໨ፂ୏ੱ‫ރ‬ԿϿाԖ΋໨ω಄ӝບᘐǶ‫ঁٿ‬ບᘐྗ߾೿ा‫؃‬೭٤ੱ‫ރ‬ा ӕਔр౜ӧ‫ٿ‬ᅿ௃ნа΢Ǵऩѝࢂр౜ӧ΋ᅿ௃‫׎‬Ǵёૈόࢂၸ୏ੱ೷ԋ‫ޑ‬Ƕ ADHD ࢂ΋ঁԐว‫ޑ܄‬ᆒઓ੯ੰǴ΋рғ൩ӸӧǴѝࢂӧόӕਔයว౜Ƕ ӧ DSM-IV ‫ ک‬ICD-10 ‫ޑ‬ບᘐྗ߾೿ा‫ރੱ؃‬Ѹ໪ӧ 7 ྃа߻൩ܴᡉ೏ᢀჸ‫ډ‬Ǵ ࣗԿԖࣴ‫ز‬ᇡࣁӧϖྃа߻൩ᔈԖܴᡉੱ‫ރ‬ǴωёΠບᘐǶ೭‫ঁٿ‬ບᘐ‫س‬಍ӚԖ ᓬલᗺǴᒧ᏷ᝄ਱‫܈‬ၨቨ᚞‫ۓޑ‬က‫ڗ‬،‫ܭ‬ᖏ‫ޑزࣴ܈׉‬ሡाǴ೚ӭᖏ‫׉‬ᙴৣ཮ᒧ ᏷ DSM-IV ‫ޑ‬ບᘐ‫س‬಍ӢࣁёаԐයว౜ሡा‫ݯ‬ᕍ‫ูٽޑ‬ǴԶό཮ᒱ՗ሡा‫ݯ‬ᕍ ‫ঁޑ‬ਢǶບᘐ΢аΒϩ‫ٰݤ‬ղ‫ࢂۓ‬ցࢂԖၸ୏ੱǴӵ݀Եቾ‫ׯރੱډ‬๓‫ޑ‬ำࡋϷ ‫ݯ‬ᕍਏ݀Ǵёૈ཮аੱ‫ރ‬ဂ࣮‫ރੱځ‬ᝄख़ำࡋ‫ׯޑ‬ᡂٰբຑ՗Ǵӧᢀჸ‫ݯ‬ᕍ‫ޑ‬ᕍ ਏ೽ϩǴёԵቾаӭय़ӛ‫܈‬٥ࠠ‫ޑ‬БԄຑ՗ੱ‫ׯޑރ‬ᡂǶ ۳۳΋ԛ‫߃ޑ‬ບᢀჸ‫ک‬ຑ՗ࢂό୼‫ޑ‬Ǵᔈ၀ଓᙫ൳ԛаዴ‫ۓ‬ບᘐǹຑ՗ਔ 6.

(14) ाԵቾ࠸η‫ޑ‬Јඵว৖ᔈԖ‫߄ޑ‬౜Ǵвಒຑ՗‫ځ‬Չࣁ߄౜ࢂց౦‫ܭ‬ӕԃស‫࠸ޑ‬ ηǴ೛‫ݤ‬ჹр౜‫ރੱޑ‬ගр‫ځ‬дඹж‫܄‬ှញǴаϷᅰໆ‫פ‬рҺՖख़ε‫ޑ‬Ӆੰੱ ‫ރ‬Ǵаխᇤບ‫ځ‬д‫ي‬ᡏ‫܈‬ᆒઓ੯ੰࣁ ADHDǶҞ߻ᗋؒԖບᘐ ADHD ‫ޑ‬Ј౛ෳ ᡍǶӢԜǴѸሡᙖշඵΚǵ‫ݙ‬ཀΚෳᡍǵԾ༤Ԅୢ‫ڔ‬ǵ‫཮ک‬ፋаຑ՗ ADHDǴ ՠࢂᖏ‫ޑ׉‬ຑ՗ᆶບᘐϝࢂ୯ሞ΢നࣁ೏ௗ‫ڙ‬ບᘐ ADHD ‫ޑ‬БԄǶຑ՗π‫ڀ‬ύ ‫ޑ‬Ծ༤ໆ߄‫཮ࢂ܈‬ፋໆ߄аϷတઓ࿶Ј౛Ꮲෳᡍத೏Ҕٰբࣁບᘐ΢ᇶշϐҔ ‫زࣴ܈‬Ҕ೼Ǵё‫ڐ‬շዴҥፄᚇঁਢ‫ޑ‬ບᘐǶջ٬ࢂ୯ሞ‫ޕ‬ӜЪς೏ௗ‫ڙ‬ϐຑ՗π ‫ڀ‬ϝࣣሡࡌҥҁβϐதኳᆶߞਏࡋǴ‫܌‬Ԗ‫ޑ‬ຑ՗ΨሡаԜࣁ኱ྗǶҞ߻Ѡ᡼ว৖ р‫ޑ‬ύЎ‫ހ‬ໆ߄хࡴǺ࢒ૈМР҆‫ހ‬Չࣁໆ߄ ȐCPRS-R:Sȑ Ϸ࢒ૈМԴৣ‫ހ‬ Չࣁໆ߄ ȐCTRS-R:Sȑ аϷР҆‫ک‬Դৣ‫܌‬༤ቪ‫ ޑ‬SNAP-IVǴԶ೭٤ύЎໆ߄ ‫ߞޑ‬ਏࡋς࿶ᕇள୯ሞᏢೌࣚ‫( ۓޭޑ‬Gau et al., 2009; Gau et al., 2008; Gau et al., 2006)Ƕ ADHD ࢂၹѲШࣚӚ୯Ъ౰Չ౗࣬྽ଯ‫ޑ‬੯ੰǶаҞ߻ DSM-IV ‫ޑ‬ບᘐ‫س‬ ಍ٰ࣮ǴᏢសය࠸η‫ޑ‬౰Չ౗εऊࢂ 5~10%ǴԋΓය߾Ԗ 4%ѰѓǶၸѐҗ‫ܭ‬٬ Ҕ‫ޑ‬ຑ՗Б‫ݤ‬όӕ ȐԾ༤ୢ‫ڔ‬ǵᖏ‫׉‬ບᘐǵᆒઓࣽບᘐ཮ፋȑǵπ‫ڀ‬όӕ ȐӚ ᅿ‫ހ‬ҁ‫ޑ‬ୢ‫ڔ‬ǵᆒઓࣽບᘐ཮ፋໆ߄ȑǵບᘐ‫س‬಍όӕ ȐICD-9ǵICD-10ǵ DSM-IIIǵDSM-III-RǵDSM-IVȑ ǵаϷঁਢٰྍόӕ Ȑᖏ‫׉‬ǵ‫୔ޗ‬ǵόӕᅿ௼ȑ ཮р౜όӕ‫ޑ‬౰Չ౗Ǵጄൎவ 0.5~17.1%ό฻Ƕ‫ٯ‬ӵ DSM-III-R ‫ޑ‬ບᘐ‫س‬಍‫ځ‬౰ Չ౗εऊࢂ 3~5%Ǵ‫ׯ‬Ҕ DSM-IV ࡕ౰Չ౗ߡගϲ೚ӭǴӢࣁ DSM-IV ‫ۓޑ‬ကၨ ቶ‫ݱ‬Ǵ఼ᇂΟঁບᘐ٥ࠠǴε೽ϩࣴ‫ز‬ว౜Ǵӝ‫ٳ‬٥ࠠऊ՞ 50~55%Ǵό஑Ј٥ ࠠऊ 30~35%Ǵၸ୏/ፂ୏٥ࠠऊ 15~20%Ƕ Կ‫ܭ‬ӧѠ᡼‫ࢬޑ‬ՉੰᏢࣴ‫ز‬Ǵ‫ॺך‬٬Ҕ኱ྗບᘐ཮ፋπ‫ڀ‬Ǵа୯ύ΋ԃભᏢ ғࣁኬҁǴҔΒ໘ࢤ‫܌ݤ‬௢ᆉ ADHD ‫ޑ‬౰Չ౗ࢂ 7.5% (Gau et al., 2005)Ƕፓࢗ୯ λ‫ډ‬୯ύᏢғ‫ ޑ‬ADHD ࣴ‫ࢂز‬٬ҔύЎҁ SNAP-IVǴਥᏵচӃа DSM-IV ‫ޑ‬ບ ᘐྗ߾‫ࢂ܈‬а 95 ԭϩКٰ،‫ࢂۓ‬ցԖ ADHDǴ‫ځ‬౰Չ౗ऊ 7~8% (Gau et al., 2008)ǴऩࢂаԴৣ‫ހ‬ൔ֋ࣁྗǴ‫ځ‬౰Չ౗ёၲ‫ ډ‬8~12% (Gau et al., 2009)Ƕ 7.

(15) 1.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ 1.2.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ ઓ࿶Ј౛Ꮲࢂᙖҗઓ࿶Ј౛ෳᡍٰຑ՗Γᜪ‫ޕޑ‬᝺ǵᇡ‫ޕ‬ǵᆶՉࣁ฻တ೽ф ૈǴԶၸѐ‫ޑ‬ઓ࿶Ј౛Ꮲࣴ‫ز‬ว౜ ADHD ‫ޑ‬Չࣁୢᚒࢂҗ‫ܭ‬တ೽фૈ౦த‫܌‬Ꮴ ठǴҞ߻ࣴ‫ز‬ᡉҢᆶ ADHD നԖᜢೱ‫ޑ܄‬ઓ࿶Ј౛фૈምᛖࢂ୺Չфૈ Ȑexecutive functionȑ‫ޑ‬౦த (Willcutt et al.,2005)Ƕ୺Չфૈ‫ۓޑ‬ကࢂᡣঁᡏӧ ཥ‫ޑ‬ᕉნᆶӭᅿϸᔈ‫ޑ‬ᒧ᏷ΠֹԋҞ኱Ꮴӛ Ȑgoal-directedȑ ‫ޑ‬ᇡ‫ޕ‬фૈǴӢ Ԝ୺Չфૈ٠ߚൂ΋‫ޑ‬ᇡ‫ޕ‬фૈǴԶ୯Ѧࣴ‫ز‬ᡉҢᆶ ADHD നԖᜢೱ‫୺ޑ܄‬Չ фૈхࡴǺ‫ڋ׭‬фૈǵೕ߾ᙯඤǵπբ૶ᏫǵᆶीฝૈΚ฻ (Pennington & Ozonoff, 1996)ǴԶ ADHD ‫୺ޑ‬Չфૈምᛖёૈ཮Ꮴठ஻‫ޣ‬ӧᏢ཰ᆶΓሞϕ୏‫ޑ‬ምᛖ (Faraone et al., 2000)ǶਥᏵၸѐ୺Չфૈ‫زࣴޑ‬ǴADHD ஻‫ޣ‬ӧຎ᝺‫ޜ‬໔ (visuo-spatial) ‫ޑ‬ምᛖКᇟ‫( ق‬verbal) ‫ޑ‬ምᛖा‫׳‬уᡉ๱ (Martinussen et al., 2005)ǴԜѦǴᆶჹྣಔ࣬КǴऩࢂෳᡍ‫ޑ‬ᜤࡋቚуਔǴADHD ஻‫୺ޑޣ‬Չфૈ ምᛖ཮ᡂ‫׳ޑ‬уܴᡉ (Young et al., 2007)Ƕ Ԗ٤Ӣη཮ቹៜ ADHD ஻‫୺ޑޣ‬ՉфૈǴхࡴඵૈǵว৖໘ࢤǵᛰ‫ނ‬ǵа Ϸᆒઓ੯ੰ‫ޑ‬Ӆੰ (comorbidity) ฻ǴԶ೭٤Ӣηࢂցૈֹӄှញ ADHD ‫୺ޑ‬Չ фૈምᛖǴ‫ ޣ܈‬ADHD ҁ‫ي‬൩཮ՔᒿԖ୺Չфૈ‫ޑ‬ምᛖǴ೭ࢂၸѐ࣬྽‫ډڙ‬ᜢ ‫ޑݙ‬᝼ᚒǴਥᏵ಍ӝϩ‫( ݋‬meta-analysis) ‫زࣴޑ‬Ǵջ٬ӧ௓‫ڋ‬ඵૈǵ᎙᠐ૈΚǵ аϷᆒઓ੯ੰ‫ޑ‬ӅੰࡕǴADHD ஻‫ޣ‬ϝԖᡉ๱‫୺ޑ‬Չфૈምᛖ (Willcutt et al., 2005)ǶќѦ࣬ჹ‫ܭ‬ၸ୏‫܈‬ፂ୏‫ރੱޑ‬ǴADHD ஻‫୺ޑޣ‬Չфૈ‫ޑ‬ምᛖ՟Я཮࡭ ុၨΦ‫ޑ‬ਔ໔ (Barkley, 2004)Ǵၸѐࣴ‫ز‬ςᡉҢԋΓ ADHD ஻‫ޣ‬ϝฅ཮Ԗ୺Չ фૈ‫ޑ‬౦த (Muller et al., 2007)ǴԶ Biederman ฻ΓӧΜԃ‫ߏޑ‬යଓᙫࣴ‫ز‬ว ౜Ǵջ٬ ADHD ‫ރੱޑ‬ςᒿਔ໔Ԗ೴‫ׯ؁‬๓Ǵՠ୺Չфૈምᛖࠅϝฅ࡭ុӸӧ (Biederman et al., 2009)Ǵ߄Ң୺Չфૈምᛖёૈࢂ΋໨੝፦኱૶ (trait marker)Ǵ 8.

(16) ၸѐ‫زࣴޑ‬ᡉҢ٬Ҕ methylphenidate ёа‫ׯ‬๓ ADHD ‫୺ޑ‬Չфૈ (Coghill et al., 2007)ǶќѦӧ຾Չ ADHD ‫ޑ‬ઓ࿶Ј౛фૈࣴ‫ز‬ਔᔈ‫ݙ‬ཀ ADHD ‫ޑ‬วੰԃइǴ ӢࣁၸѐԖࣴ‫ز‬ᡉҢఁวੰ‫ ޑ‬ADHD ӧᇟ‫ق‬ඵ୘ (verbal IQ) ᆶᏹբඵ୘ (performance IQ)Ǵ‫߄ځ‬౜೿཮КԐวੰ‫ޑ‬஻‫ٰޣ‬ளৡǴёૈ߄Ңวੰԃइ཮ቹៜ ADHD ஻‫ޑޣ‬ઓ࿶Ј౛фૈ (Faraone et al., 2006)Ƕ ᗨฅၸѐᇡࣁ ADHD ஻‫୺ޣ‬Չфૈ‫ޑ‬ምᛖ཮வ‫ูٽ‬ය΋‫ߙډុ࡭ޔ‬Ͽԃ යǴՠჹ‫ߙܭ‬Ͽԃ ADHD ஻‫୺ޑޣ‬Չфૈࣴ‫ز‬ϝฅόӭǴԶЪ౜Ԗ‫่݀زࣴޑ‬ ۶Ԝϐ໔ΨԖࡐε‫ޑ‬ৡ౦‫܄‬Ǵᖐ‫ٰٯ‬ᇥǴBarkley ฻Γว౜ߙϿԃ ADHD ஻‫ޣ‬٠ ؒԖܴᡉ‫ޑ‬πբ૶Ꮻ‫܈‬ϸᔈ‫( ڋ׭‬response inhibition) Бय़‫ޑ‬ምᛖ (Barkley et al., 2001)ǴӢԜჹ‫ߙܭ‬Ͽԃ ADHD ஻‫୺ޑޣ‬Չфૈᔈ၀ሡा຾΋‫زࣴޑ؁‬Ƕ. 1.2.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ ќѦ΋ঁᆶઓ࿶Ј౛фૈԖᜢ‫ޑ‬᝼ᚒ߾ࢂϣ߄౜ࠠ ȐendophenotypeȑǶԖ ձ‫ܭ‬໺಍аՉࣁ੝ቻ‫ۓ‬က ADHD ‫߄ޑ‬౜ࠠǴ߈ԃٰࣴ‫ز‬໼ӛ‫פ‬р ADHD ‫ޑ‬ϣ߄ ౜ࠠǴаߡ‫׳‬ௗ߈೷ԋ ADHD ‫ޑ‬ठੰচӢǶϣ߄౜ࠠ‫ۓޑ‬ကࢂࡰКੱ‫߄کރ‬ቻ ‫׳‬ௗ߈ࢌᖏ‫׉‬੯ੰ‫ޑ‬ғ‫ނ‬ᏢੰӢϐ߄౜ࠠǴԶ‫کڙ‬Ԝ੯ੰӕኬ‫ޑ‬΋ঁ‫܈‬ӭঁܰ‫ڙ‬ ‫୷܄‬Ӣ‫ޑ‬ቹៜǶADHD ϣ߄౜ࠠѸ໪಄ӝаΠ‫ޑ‬ा‫( ؃‬Doyle et al., 2005)Ǻ(1) ‫ک‬ ADHD ӕਔӸӧǴՠࢂόૈӧԖ ADHD ບᘐ‫ޑ‬஻‫ޣ‬΋‫ۓ‬ӸӧԜϣ߄౜ࠠǴΨ൩ ࢂᇥԖଯ‫ܭ‬΋૓Γ‫ޑ‬К‫ٯ‬ӧ ADHD ஻‫ޣ‬р౜Ԝϣ߄౜ࠠǴՠόѸฅ ADHD ஻‫ޣ‬ ΋‫ۓ‬ӸӧԜ߄౜ࠠ<(2) ёа೏‫ڀ‬Ԗ‫ؼ‬ӳीໆ੝፦ Ȑхࡴߞਏࡋȑ‫ޑ‬ෳໆπ‫܌ڀ‬ ෳໆ; (3)Ѹ໪ाԖᒪ໺‫ޑ‬᛾Ᏽ; (4) ‫ ک‬ADHD ाԖৎ௼‫܄‬Ϸ୷Ӣ‫ޑ‬ख़᠄ǴऩؒԖ ৎ௼ᆫ໣‫܄‬ख़᠄Ǵࣴ‫ޣز‬ёૈ‫ډפ‬ғ‫ނ‬Ꮲ߄౜ࠠ୷ӢǴՠࢂค‫ ډפݤ‬ADHD ‫ޑ‬ ୷ӢǶ΋૓Զ‫ق‬Ǵઓ࿶Ј౛фૈǵઓ࿶ቹႽǵаϷઓ࿶ႝғ౛฻Бय़೿ёаբࣁ ADHD ‫ޑ‬ϣ߄౜ࠠǴՠӧ೭٤ϣ߄౜ࠠύǴઓ࿶Ј౛фૈ࣬ჹࢂሽ਱Кၨߡ‫ە‬Ǵ ԶЪؒԖߟΕ‫܄‬ᔠࢗ‫ޑ‬ӒᓀǴӢԜς೏ ADHD ࣬ᜢࣴ‫ز‬Ꮲ‫ޣ‬ᇡࣁࢂന፾ӝբࣁ 9.

(17) ࣴ‫ ز‬ADHD ‫ޑ‬ϣ߄౜ࠠ (Doyle et al., 2005)Ƕ җ߻ॊ 1.2 (a)‫ࢤޑ‬ပ‫ॺך‬ёа‫ޕ‬ၰǴADHD ஻‫཮ޣ‬ӝ‫ٳ‬Ԗ୺Չфૈ‫ޑ‬ምᛖǴ ӢԜ୺ՉфૈምᛖΨ೏ᇡࣁࢂ ADHD ёૈ‫ޑ‬ϣ߄౜ࠠϐ΋Ƕၸѐࣴ‫ز‬ᡉҢǴ୺ Չфૈ‫ޑ‬ᒪ໺౗ (heritability) ࣁ 0.72 (Fan et al.,2001)ǴӢԜࢂ΋ᅿ཮Ԗৎ௼ᒪ໺ ‫ޑ܄‬ઓ࿶Ј౛ᏢфૈምᛖǶќѦǴନΑ ADHD ஻‫ޣ‬ҁ‫ڀي‬Ԗ୺Չфૈ‫ޑ‬ምᛖǴ ၸѐ‫زࣴޑ‬Ψว౜Ǵӧ ADHD ஻‫ޣ‬ৎ৥Ǵ҂஻Ԗ ADHD ‫ޑ‬ᒃឦύΨԖ‫ݙ‬ཀΚ௓ ‫( ڋ‬D. I. Slaats-Willemse et al.,2007) ‫ک‬ϸᔈ‫( ڋ׭‬D. Slaats-Willemse et al., 2003) Бय़‫ޑ‬౦தǴӧሦᎦࣴ‫(ز‬adoption studies)ύǴᆶᎦР҆࣬КၨǴADHD ஻‫ޑޣ‬ ғР҆೏ว౜ӧຎ᝺‫ݙ‬ཀΚ (visual attention) ᆶϸᔈਔ໔ (reaction time) ‫߄ޑ‬ ౜ၨৡ (Alberts-Corush et al., 1986)ǴќѦ Nigg ฻Γ‫߾زࣴޑ‬ว౜ǴADHD ஻‫ޣ‬ ‫ޑ‬ғР҆ӧຎ᝺‫ޜ‬໔‫ۓ‬ӛբ཰ (visuospatial orienting task) Ԗၨৡ‫ޑ‬ϸᔈ (Nigg et al., 1997)Ǵҗ΢ॊ‫زࣴޑ‬ёа௢ፕ ADHD ‫୺ک‬Չфૈምᛖ‫ڀ‬Ԗৎ௼ख़᠄‫܄‬Ƕ ՠΨԖ‫زࣴޑ‬ൔ֋٠҂ว౜ ADHD ஻‫ޑޣ‬ᒃឦԖ୺ՉфૈБय़‫ޑ‬౦த (Asarnow et al., 2002; Murphy & Barkley, 1996)Ǵ೭ёૈࢂӢࣁၸѐ‫زࣴޑ‬Ьा೿ࢂѝҔൂ ΋ෳᡍٰຑ՗୺ՉфૈǴલЮ٬Ҕֹ᏾‫ޑ‬኱ྗϯπ‫ٰڀ‬ຑ՗ ADHD ஻‫ځޣ‬҂ว ੰᒃឦ‫ޑ‬᏾ᡏ୺ՉфૈǶ ӧઓ࿶Ј౛фૈБय़ǴନΑ୺Չфૈёаբࣁ ADHD ‫ޑ‬ϣ߄౜ࠠϐѦǴќ Ѧ΋ঁёૈ‫ޑ‬ϣ߄౜ࠠࢂຎ᝺૶Ꮻ (visual memory)Ƕၸѐࣴ‫ز‬ᡉҢ ADHD ஻‫ޣ‬ Ԗࡐܴᡉ‫૶ޑ‬Ꮻфૈምᛖ (Rapport et al., 2001)ǴԶຎ᝺૶Ꮻࢂࡰ‫ڙ‬၂‫ޣ‬ӧֹ࣮΋ ঁፄᚇ‫ޑ‬კ‫׎‬ϐࡕǴѸ໪ஒკ‫૶׎‬ՐǴϐࡕाᙖ๱ӣᏫᒧ‫҅ڗ‬ዴ‫ޑ‬კ‫׎‬ଛჹǴӢ Ԝຎ᝺૶Ꮻჹ‫ڙܭ‬၂‫ࢂޣ‬΋ঁሡाଯࡋၮҔЈࡘωૈֹԋ‫ޑ‬ෳᡍ (Berman et al., 1999)ǶԖ൳Бय़‫ޑ‬᛾ᏵЍ࡭຾΋‫زࣴ؁‬ຎ᝺૶Ꮻёаբࣁ ADHD ‫ޑ‬ϣ߄౜ࠠǴ ಃ΋ǴԖཇٰཇӭ‫ޑ‬ൔ֋ᡉҢ ADHD ஻‫ޣ‬ӕਔӝ‫ٳ‬Ԗຎ᝺૶Ꮻ‫ޑ‬ምᛖǴхࡴ‫ޜ‬ ໔ᒣᇡ૶Ꮻ (spatial recognition memory) (Kempton et al., 1999)ǵ‫ۯ‬ᒨኬҁଛჹ (delayed matching to sample) (Barnett, Maruff, & Vance, 2009)ǵ‫׎‬ᄊᒣᇡ૶Ꮻ (pattern recognition memory) (S. M. Rhodes et al.,, 2004)ǵаϷଛჹ࣬ᜢᏢಞ 10.

(18) (paired associates learning) (H. T. Chang et al., 1999)฻Бय़Ǵ΢ॊ೭٤ࣴ‫ز‬೿Ѝ࡭ ADHD ஻‫ޑޣ‬ઓ࿶Ј౛фૈምᛖх֖Αຎ᝺૶Ꮻ‫ޑ‬ୢᚒǹಃΒǴϣ߄౜ࠠѸ໪ ाૈᒪ໺ǴԶၸѐࣴ‫ز‬ᡉҢຎ᝺૶Ꮻ‫ޑ‬ᒪ໺౗ࣁ 0.53ǴࣗԿଯ‫ܭ‬ᇟ‫کق‬ག‫ૻ۔‬৲ ೀ౛ೲࡋ‫ޑ‬ᒪ໺౗ (Alarcon et al., 1998)ǹಃΟǴmethylphenidate ჹ‫ ܭ‬ADHD ஻ ‫ޑޣ‬ຎ᝺૶ᏫምᛖԖܴᡉ‫ׯޑ‬๓ਏ݀ (S. M. Rhodes et al., 2004; S. M. Rhodes et al., 2006)ǶᗨฅԖ΢ॊ‫زࣴޑ‬Ѝ࡭ຎ᝺૶Ꮻёૈࢂ ADHD ‫ޑ‬ϣ߄౜ࠠǴՠ‫ډ‬Ҟ ߻ࣁЗǴШࣚ΢ᗋؒԖҺՖ΋ঁৎ௼ࣴ‫ز‬᛾ჴ ADHD ஻‫ځޣ‬҂วੰ‫ޑ‬ᒃឦΨӕ ਔԖຎ᝺૶Ꮻ‫ޑ‬ምᛖǶ. 1.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ ୺Չфૈࢂ ADHD ёૈ‫ޑ‬ϣ߄౜ࠠǴԶၟ୺ՉфૈԖᜢ‫ޑ‬ઓ࿶໺Ꮴ‫ނ‬፦Ь ाࣁ catecholaminergic ‫س‬಍ (A. F. T. Arnsten & B.-M. Li, 2005)ǴӢԜ೸ၸբҔӧ catecholaminergic ‫س‬಍‫ޑ‬ᛰ‫ނ‬Ǵᔈ၀Ԗёૈ‫ׯ‬๓ ADHD ୺Չфૈ‫ޑ‬ምᛖǶҞ߻ӧ Ѡ᡼ჹ‫ ܭ‬ADHD ‫ݯޑ‬ᕍᛰ‫ނ‬ЬाԖ‫ٿ‬ᅿǴ΋ᅿࢂ methylphenidateǴќѦ΋ᅿ߾ ࢂ atomoxetineǶ‫ځ‬ύ atomoxetine ࢂ΋ঁଯࡋᒧ᏷‫҅ޑ܄‬๝΢ဏનӆ֎ԏ‫ڋ׭‬Ꮚ (highly selective noradrenaline reuptake inhibitor)Ǵό཮բҔ‫ځܭ‬Ѭ‫ޑ‬ઓ࿶໺Ꮴ‫ނ‬፦ (Simpson & Perry, 2003)Ƕ‫܌‬а atomoxetine ёаගଯ߻ᚐယ‫҅ޑ‬๝΢ဏન‫ޑ‬ᐚ ࡋǴՠό཮ჹ‫ ܭ‬nucleus accumbens ԖҺՖቹៜ (Bymaster et al., 2002)ǴԶ nucleus accumbens ࢂᆶઓ࿶ᑫᏟᏊϐԋ᠅‫࣬܄‬ᜢ‫ޑ‬တ೽୔ୱ (Koob & Le Moal, 1997)Ǵ ӢԜǴatomoxetine ࢂಃ΋ঁӧ 2002 ԃ೏ऍ୯ FDA ೯ၸҔٰ‫ݯ‬ᕍ ADHD ‫ߚޑ‬ύ ኰઓ࿶ᑫᏟᏊǶԶၸѐՋБ (Caballero & Nahata, 2003) ‫ک‬Ѡ᡼ (Gau et al., 2007) ‫֡زࣴޑ‬ᡉҢǴatomoxetine ёаԖਏ‫ׯ‬๓ ADHD ‫ޑ‬ᖏ‫ރੱ׉‬ǴӕਔΨό཮ჹ‫ܭ‬ ᅵ઀ౢғό‫ޑؼ‬ቹៜ (Prasad & Steer, 2008)Ǵatomoxetine ჹ‫ ܭ‬ADHD ӅੰԖ‫ܜ‬ ┢ (Allen et al., 2005) ‫ک‬ขቾ (Geller et al., 2007) ‫ޑ‬஻‫ޣ‬ΨԖКၨӳ‫ޑ‬ᕍਏǴӢ Ԝ atomoxetine ӧ ADHD ‫ޑ‬ᖏ‫ݯ׉‬ᕍ΢‫ת‬ᄽΜϩख़ा‫فޑ‬ՅǶ 11.

(19) Faraone ฻Ꮲ‫ࡌޣ‬᝼୺ՉфૈምᛖΨᔈ၀೏ຎࣁ ADHD ‫ݯޑ‬ᕍҞ኱ϐ΃ (S. V. Faraone et al., 2005)Ƕᗨฅၸѐࣴ‫ز‬ᡉҢ୺Չфૈᆶ catecholaminergic ‫س‬಍ύ ‫҅ޑ‬๝΢ဏનԖᜢ (L. A. Newman, Darling, & McGaughy, 2008)ǴՠҞ߻ѝԖࡐϿ ࣴ‫ز‬௖૸ atomoxetine ჹ‫ ܭ‬ADHD ୺Չфૈምᛖ‫ޑ‬ᕍਏǶ୏‫زࣴޑނ‬ᡉҢ atomoxetine ёа‫ׯ‬๓ϸᔈਔ໔ (five-choice serial reaction time) (Blondeau & Dellu-Hagedorn, 2007)ǵफ़եፂ୏‫( ܄‬Robinson et al., 2008)ǵаϷ‫ׯ‬๓‫ݙ‬ཀΚ (L. A. Newman et al., 2008)ǶΓᜪ‫߾زࣴޑ‬ว౜Ǵatomoxetine ёа෧Ͽ଼ந‫ڙ‬၂‫ޣ‬ (Samuel R. Chamberlain et al., 2006) ᆶԋΓ ADHD ஻‫( ޣ‬S. R. Chamberlain et al., 2007) ϐଶЗૻဦ‫ޑ‬ϸᔈਔ໔ (stop-signal reaction time)ǴќѦჹ‫ܭ‬ԋΓ ADHDǴ ӧ࿶ၸΟຼ (T. Spencer et al., 1998) ‫ک‬Μຼ (S. V. Faraone et al., 2005) ‫ޑ‬ atomoxetine ‫ݯ‬ᕍϐࡕǴ஻‫ૈڋ׭ޑޣ‬Κ཮ᡉ๱ቚуǶՠၸѐԖज़‫ޑ‬ၗ਑ΨᡉҢǴ atomoxetine ჹ‫ܭ‬ԋΓ ADHD ஻‫ݙޑុ࡭ޣ‬ཀΚ (sustained attention) (T. Spencer et al., 1998)ǵ‫ݙ‬ཀΚᙯඤբ཰ (attentional set shifting) (T. Spencer et al., 1998)ǵа Ϸ‫ޜ‬໔πբ૶Ꮻ (spatial working memory) (S. R. Chamberlain et al., 2007)٠ؒԖ ܴᡉ‫ׯޑ‬๓ਏ݀Ƕ ᗨฅᖏ‫׉‬΢ܺҔ atomoxetine ‫ ูٽޑ‬ADHD ஻‫ޣ‬ཇٰཇӭǴՠΜϩલЮ௖૸ atomoxetine ჹ‫୺ูٽܭ‬ՉфૈբҔ‫زࣴޑ‬Ǵ໻Ԗ΋ጇӃ០ࣴ‫ز‬ว౜ atomoxetine ჹ‫ ูٽܭ‬ADHD ஻‫זޑޣ‬ೲຎ᝺ૻ৲ೀ౛ෳᡍ (Rapid Visual Information Processing task) ‫ڀ‬Ԗ‫ׯ‬๓‫ޑ‬ਏ݀ (Barton et al., 2005)Ǵᗨฅ߻ॊ‫زࣴޑ‬Ψӕਔຑ ՗஻‫ځޣ‬Ѭ‫୺ޑ‬ՉфૈǴӵ‫ݙ‬ཀΚᙯඤբ཰ (attentional set shifting)ǵ‫ޜ‬໔ीฝૈ Κ (spatial planning)ǵаϷϸᔈਔ໔ (reaction time)Ǵՠբ‫ޣ‬٠҂ග‫ ډ‬atomoxetine ჹ‫ܭ‬೭٤୺Չфૈ‫ޑ‬ᕍਏࢂӵՖǴԜѦǴҗ‫ܭ‬೭ঁӃ០ࣴ‫ز‬ѝԖԏ໣ΑΐӜ஻ ‫ޣ‬Ǵ‫ڙ‬ज़‫ܭ‬ኬҁኧၨϿǵᔠ‫ۓ‬Κ (power) ό‫ޑى‬ጔࡺǴ‫܌‬а‫่݀زࣴځ‬٠ค‫ݤ‬ ჹ‫ ܭ‬atomoxetine ӧ‫ ูٽ‬ADHD ஻‫୺ޑޣ‬Չфૈᕍਏ΢଺рޭ‫่ޑۓ‬ፕǴѝаጓ ‫ߞٰޣ‬ว߄Ǵ҂ٰϝሡा‫׳‬εೕኳ‫ٰزࣴޑ‬௖૸ atomoxetine ჹ‫ ูٽ‬ADHD ஻‫ޣ‬ ୺Չфૈምᛖ‫ޑ‬ᕍਏǶ 12.

(20) ନΑ୺ՉфૈምᛖϐѦǴ߻ॊ 1.2 (b) ࿯‫ࢤޑ‬ပҭςඔॊ ADHD ஻‫ޣ‬ёૈӕ ਔӝ‫ٳ‬Ԗຎ᝺૶ᏫምᛖǴԶၸѐ‫زࣴޑ‬ᡉҢຎ᝺૶Ꮻёૈᆶύኰઓ࿶‫҅ޑ‬๝΢ဏ ન‫س‬಍‫ڀ‬Ԗ࣬ᜢ‫܄‬ǴӢࣁύኰઓ࿶҅๝΢ဏન‫ޑ‬ញ‫཮ܫ‬ගϲ૶ᏫૈΚ (Gibbs, 2008)Ǵ୏‫߾زࣴޑނ‬ᡉҢ྽‫ڙ‬၂୏‫ނ‬ӧ຾Չ‫ޜ‬໔૶Ꮻ (spatial memory) ෳᡍ ਔǴ҅๝΢ဏન‫ޑ‬ᐚࡋ཮ӕ‫؁‬ቚу (Rossetti & Carboni, 2005)Ǵ߄Ң҅๝΢ဏન ёૈӧຎ᝺‫ޜ‬໔ૻ৲ (visuo-spatial information) ᓯӸ‫ૈޑ‬Κ΢‫ת‬ᄽख़ा‫ف‬ՅǴќ Ѧ Clayton ฻Γว౜྽ࢲϯԴႵύኰઓ࿶‫҅ޑ‬๝΢ဏન‫س‬಍ਔǴёаε൯‫ׯ‬๓ຎ ᝺૶Ꮻ‫ૈޑ‬Κ (Clayton & Williams, 2000)ǶԿ‫ܭ‬ӧΓᜪ‫زࣴޑ‬Бय़ǴMoor ฻Γ ว౜ऩ๏ϒ଼ந‫ڙ‬၂‫ޣ‬ᓉે‫ݙ‬৔҅๝΢ဏનǴ཮ᡉ๱ගϲ‫ځ‬ຎ᝺ᒣᇡ૶Ꮻ (visual recognition memory) ૈΚ (Moor et al., 2005)ǶନԜϐѦǴ҅๝΢ဏનΨᆶ ‫ݙ‬ཀΚԖஏϪ‫ޑ‬ᜢ߯ (J. T. Coull et al., 2004)ǴऩࢂεတҜ፦‫҅ޑ‬๝΢ဏનᐚࡋό ‫ى‬Ǵஒ཮Ꮴठܴᡉ‫ݙޑ‬ཀΚό‫ޑى‬౜ຝ (Carli et al., 1983)Ƕ ᗨฅ҅๝΢ဏનӧຎ᝺૶ᏫБय़‫ת‬ᄽख़ा‫ف‬ՅǴՠၸѐ٠ؒԖ࣬ᜢЎ᝘௖૸ atomoxetine ჹΓᜪຎ᝺૶Ꮻ‫ޑ‬բҔǴѝԖϿኧ‫ޑ‬൳ጇ୏‫زࣴނ‬ᡉҢǴatomoxetine ёа෧Ͽຎ᝺ᒣᇡ૶Ꮻ (Tzavara et al., 2006) аϷຎ᝺୔ᒣෳᡍ (visual discrimination test) ‫ޑ‬ᒱᇤ౗ (Seu et al., 2009)ǴӢԜԖѸा຾Չࣴ‫ز‬а௖઩ atomoxetine ჹ‫ ูٽܭ‬ADHD ஻‫ޣ‬ຎ᝺૶Ꮻምᛖ‫ݯޑ‬ᕍਏ݀Ƕ. 1.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ ᜢ‫ ܭ‬ADHD ‫ޑ‬ቹႽᏢࣴ‫ز‬ว৖Ǵத‫زࣴޑـ‬БԄёϩࣁ่ᄬ‫܄‬Ϸфૈ‫܄‬ቹ ႽᏢࣴ‫ز‬Ǵ่ᄬ‫زࣴ܄‬தа MRI ȐਡᅶӅਁȑ ϩ‫݋‬တ೽ᡏᑈǵҜ፦ࠆࡋǴԶ ཥ‫ޑ‬ᘉණ஭ໆ೷ቹ (diffusion tensor imagingǴDTI) ‫ೌמ‬ёаϩ‫݋‬қ፦‫ޑ‬ઓ࿶‫״‬ ᖄ่Ƕфૈ‫زࣴ܄‬தа PET Ȑ҅η೷ቹȑ ‫ ܈‬fMRI Ȑфૈ‫܄‬ਡᅶӅਁȑ ϩ‫݋‬ တ೽Ոనឲࢬ‫ޑ‬ᡂϯǴа໔ௗள‫ޕ‬ઓ࿶ࢲ୏‫ރޑ‬ᄊǶ೚ӭ่ᄬ‫زࣴ܄‬΋ठӦว౜ ADHD ஻‫ޣ‬೚ӭတ୔‫ޑ‬ᡏᑈၨ҅தΓλǴхࡴεတ‫߻ޑ‬ᚐယ (prefrontal cortex) 13.

(21) (Castellanos et al., 2001)ǵ‫׀‬ਡ (caudate) (Castellanos et al., 2001; Castellanos et al., 2002)ǵᇇқౚ (pallidum) (Castellanos et al., 1996)ǵङ߻ୁԌ஥Ҝ፦ (dorsal anterior cingulate cortex) (dACC) (Larry J. Seidman et al., 2005)Ϸ૊टᡏ )corpus callosum) (Larry J. Seidman et al., 2005)ǴаϷλတ‫ࡕޑ‬Πယ (posterior inferior lobules)Ϸ૪೽ (vermis) (Castellanos et al., 1996)Ƕന߈‫زࣴޑ‬ᡉҢ ADHD ‫ޑ‬εတ Ҝ፦ԋዕၨఁǴӢࣁ΋૓‫ูٽ‬ᚐယεတҜ፦‫ࡋࠆޑ‬εऊӧ 7 ‫ ډ‬8 ྃѰѓ཮ၲ‫ډ‬ഗ ᆄ (peak)Ǵՠ ADHD ‫ޑ‬ᚐယҜ፦ࠆࡋεऊा‫ ډ‬11 ྃѰѓωၲ‫ډ‬ഗᆄǴԶ‫ډ‬Αߙ ϿԃਔයǴ΋૓Γ‫ޑ‬εတҜ፦཮໒‫ۈ‬ᡂᖓǴՠࢂ ADHD ஻‫ޣ‬ऩؒԖௗ‫ݯڙ‬ᕍǴ ‫ځ‬εတҜ፦ᡂᖓ‫ޑ‬ೲࡋ཮‫( ז׳‬Shaw et al., 2009)ǴӢԜ ADHD ‫ޑ‬஻‫ޣ‬ӧတ೽ว ৖Бय़ዴჴԖܴᡉ‫ޑ‬౦தᡂϯǶ ᗨฅ ADHD ёૈᆶတ೽೚ӭ୔ୱ‫ޑ‬౦தԖᜢǴ‫ځ‬ύനख़ा‫୔ޑ‬ୱࣁ߻ᚐ ယǴӕਔ߻ᚐယΨӧΓᜪ‫୺ޑ‬ՉфૈБय़‫ת‬ᄽख़ा‫فޑ‬Յ (Arnsten, 2009)ǶਥᏵ ઓ࿶ှওᏢ‫ޑ‬Տ࿼Ǵ߻ᚐယΞёаಒϩԋѤঁфૈ΢όӕ‫୔ޑ‬ୱǴхࡴΑङѦୁ ߻ᚐယҜ፦ (dorsolateral prefrontal cortexΔDLPFC)ǵϣୁ߻ᚐယҜ፦ )medial prefrontal cortexΔMPFC)ǵ౳ᆂᚐယҜ፦ )orbitofrontal cortexΔ (OFC)ǵаϷဎ Ѧୁ߻ᚐယҜ፦ )ventrolateral prefrontal cortexΔVLPFC)Ǵ‫ځ‬ύ DLPFC ᆶՉ୏‫ޑ‬ ीฝ (action planning) Ԗᜢ (Fuster, 2002)ǴMPFC ᆶӧཥ‫ڻ‬௃ნΠ‫ݙޑ‬ཀΚᙯ౽ (shifting under novel situations) Ԗᜢ (Konishi et al., 2010)ǴOFC ᆶൔᓭЇᏤ‫ޑ‬Չ ࣁ (reward-guided behavior) Ԗᜢ (Price, 1999)ǴVLPFC ߾ᆶ‫ޜ‬໔ૻ৲‫ޑ‬ೀ౛ (spatial information processing) Ԗᜢ (Wolf et al., 2009)Ƕ ന߈җ‫ܭ‬ਡᅶӅਁ‫ޑೌמ‬ว৖ǴDTI ёаග‫׳ٮ‬ӭᜢ‫ܭ‬တϣઓ࿶ᠼᆢ‫وޑ״‬ ӛϷֹ᏾‫ޑ܄‬ၗૻǴаठૈ୼‫ޔ‬ௗև౜တ೽୔ୱϐ໔‫่ޑ‬ᄬ΢‫ޑ‬ᖄ่ǴԶӧ DTI ‫زࣴޑ‬ύ fractional anisotropy (FA)൩࿶த೏Ҕٰբࣁεတқ፦ಒ༾่ᄬ‫ֹޑ‬᏾‫܄‬ (microstructure integrity) ‫ࡰޑ‬኱ (Johansen-Berg & Behrens, 2009)Ƕϐ߻‫ ޑ‬DTI ࣴ‫ز‬ว౜ӧᚐယદ‫ރ‬ᡏ (frontostriatal tracts) (Ashtari et al., 2005; Casey et al., 2007; A. Konrad et al., 2010; Pavuluri et al., 2009)ǵλတ (Ashtari et al., 2005)ǵҜ 14.

(22) ፦ૉࢊၡ৩ (corticospinal tract) (Hamilton et al., 2008)ǵаϷ΢ᕵՉᠼᆢ‫״‬ (superior longitudinal fasciculus) (A. Konrad et al., 2010)฻୔ୱǴ‫ูٽ‬ϷߙϿԃ ADHD ஻‫ޑޣ‬қ፦ಒ༾่ᄬ‫ֹޑ‬᏾‫܄‬ԖલཞǶӧ΢ॊ೭٤ ADHD ஻‫ޣ‬ёૈр౜ ઓ࿶ᖄ่લཞ‫ޑ‬တ೽୔ୱύǴаᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ᖄ่લཞࣁന΋ठ‫ޑ܄‬ว౜ (Liston et al., 2011)ǶନΑᆶ ADHD ‫ޑ‬ບᘐԖ࣬ᜢϐѦǴΨԖࣴ‫ز‬຾΋‫؁‬ว౜દ ‫ރ‬ᡏ‫ ޑ‬FA ኧॶᆶ‫ ูٽ‬ADHD ஻‫ރੱޑޣ‬ᝄख़ำࡋԖᜢǶ ѝԖϿኧ‫زࣴޑ‬௖૸ᚐယદ‫ރ‬ᡏઓ࿶ᖄ่ᆶ୺Չфૈϐ໔‫ޑ‬ᜢ߯ǴListon ฻ Γว౜ᚐယદ‫ރ‬ᡏઓ࿶ᖄ่‫ޑ‬ԋዕ཮ගϲ଼ந‫ڙ‬၂‫ޣ‬ӧֹԋ go/no-go task ‫ޑ‬ਏ ౗ (efficiency) (Liston et al., 2006)ǴќѦ Casey ฻Γ‫زࣴޑ‬Ψว౜Ǵᚐယદ‫ރ‬ᡏ ‫ ޑ‬FA ኧॶཇଯǴ‫ ูٽ‬ADHD ஻‫ޣ‬ӧ຾Չ go/no-go task ਔ‫ޑ‬ፂ୏‫཮܄‬Πफ़ (Casey et al., 2007)ǴfMRI ΨᡉҢᚐယદ‫ރ‬ᡏ‫ࢲޑ‬ϯᆶ ADHD ஻‫୺ޑޣ‬Չ௓‫( ڋ‬executive control) (K. Konrad et al., 2006) аϷբ཰ᙯඤ (task switching) (Dibbets et al., 2010) ԖᜢǶ Ҟ߻ჹ‫ ܭ‬ADHD ஻‫୺ޑޣ‬Չфૈምᛖ‫ޑ‬ઓ࿶่ᄬલཞᐒᙯᗋӧ߃‫ޑزࣴ؁‬ ໘ࢤǴԶЪ DTI ‫ૻޑ‬ဦёૈ཮‫ډڙ‬ઓ࿶ᠼᆢҬΰ (crossing fibers) ‫ޑ‬υᘋǴаठ ค‫҅ݤ‬ዴຑ՗ઓ࿶ᖄ่‫ֹޑ‬᏾‫܄‬ǴӢԜ҂ٰϝሡा‫׳‬ଯှ‫ޑࡋ݋‬ਡᅶӅਁ‫מޑ‬ ೌǴаߡૈ‫׳‬ుΕӦ௖૸ᚐယદ‫ރ‬ᡏӧ ADHD ஻‫୺ޑޣ‬Չфૈምᛖ‫ת܌‬ᄽ‫فޑ‬ ՅǶ. 1.5 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ 1.5.1 DAT1 ୷Ӣᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫࣬ޑ‬ᜢ‫زࣴ܄‬ ADHD ឦ‫ܭ‬ፄᚇ‫ޑ‬ᒪ໺‫܄‬੯ੰǴΨ൩ࢂᇥ ADHD ёૈ‫ࡐک‬ӭ୷Ӣ೿Ԗᜢᖄ ‫܄‬Ǵ೭٤ঁձ‫୷ޑ‬Ӣᗨฅό཮‫ޔ‬ௗᏤठ੯ੰǴՠ཮ቚу‫܈‬෧Ͽᑡੰ‫ޑ‬ᐒ཮ǴԶ ADHD ёૈࢂ೭٤୷ӢᆶӚᅿᕉნӢηҬϕբҔ‫܌‬ౢғ‫่݀ޑ‬ǶҞ߻‫࣬ޑ‬ᜢ‫܄‬ ϩ‫زࣴޑ݋‬ᡉҢ‫ޑ‬ёૈংᒧ୷Ӣ (candidate gene) ᅿᜪߚதӭǴՠ໣ύӧ‫ঁٿ‬Ь 15.

(23) ा‫ޑ‬ઓ࿶໺Ꮴ‫س‬಍ǺӭЃữ (dopamine) ‫س‬಍ǴϷ҅๝΢ဏન (norepinephrine) ‫س‬ ಍Ǵ‫ځ‬ύ DAT1 ࢂനத೏ග‫ ޑډ‬ADHD ংᒧ୷ӢǶ DAT1 ୷ӢՏ‫ࢉܭ‬Յᡏ 5P15.33Ǵҗ 15 ঁѦᡉη (exons) ᆶ 14 ঁϣᡉη (introns) ‫܌‬ಔԋǴελऊࣁ 52kbǴԖ൳Бय़‫ޑ‬᛾ᏵЍ࡭ DAT1 ࢂ ADHD ‫ޑ‬ठੰ ୷ Ӣ Ǻ ಃ ΋ Ǵ Ҟ ߻ ‫ ݯ‬ᕍ ADHD ‫ ޑ‬ᛰ ‫ ނ‬ύ ٬ Ҕ ന ӭ ‫ ࢂ ޑ‬ύ ኰ ઓ ࿶ ᑫ Ꮯ Ꮚ methylphenidateǴԶ methylphenidate ൩ࢂᙖ๱ߔᘐ dopamine transporter (DAT) а ၲ‫ݯډ‬ᕍਏ݀ (Volz, 2008)ǹಃΒǴၸѐઓ࿶ቹႽᏢࣴ‫ز‬ᡉҢӧ‫ ูٽ‬ADHD ঁਢ ‫ޑ‬တ೽ DAT ஏࡋК଼நჹྣಔଯ 50% (Cheon et al., 2003)ǴќѦΨԖࣴ‫ز‬ᡉҢԋ Γ ADHD ঁਢ‫ޑ‬တ೽ DAT ஏࡋК଼நჹྣಔଯ 17% (Dresel et al., 2000)ǹಃΟǴ ӧ٬Ҕ methylphenidate ‫ݯ‬ᕍΑΟຼϐࡕǴADHD ঁਢ‫ޑ‬တ೽ DAT ஏࡋΠफ़εऊ 74.7% (Vles et al., 2003)ǴӧଶЗ٬Ҕ methylphenidate ϐࡕǴDAT ‫ޑ‬ஏࡋ΢ϲΑ 64% (Feron et al., 2005)ǹಃѤǴDAT1 konck-out ‫ޑ‬ԴႵёаբࣁ ADHD ӝ፾‫ޑ‬ ୏‫ނ‬ኳԄ (Trinh et al., 2003)Ƕᆕӝа΢൳Бय़‫ޑ‬᛾ᏵǴЍ࡭ DAT1 ୷Ӣዴჴࢂ ADHD ‫ޑ‬ख़ाংᒧ୷ӢǶ ၸѐ‫زࣴޑ‬Ьा໣ύӧ DAT1 ୷Ӣӧ 3´-untranslated region (3'UTR)‫ޑ‬ᡂ౦ (variable number of tandem repeatǴVNTR)ǴӢࣁ೭ঁՏ࿼‫୷ޑ‬Ӣᡂ౦ᆶᆒઓ੯ ੰ ‫ ڀ‬Ԗ ᡉ ๱ ࣬ ᜢ ‫ ܄‬Ǵ х ֖ ᆒ ઓ ϩ ຋ ੱ (Prata et al., 2009) ᆶ ଚ ᆒ ٩ ᒘ (Samochowiec et al., 2006)Ƕᗨฅ Cook ฻Γӧ 1995 ԃಃ΋ԛว౜ DAT1 ୷Ӣ‫ޑ‬ 3´VNTR ᆶ ADHD ‫ڀ‬Ԗܴᡉ‫࣬ޑ‬ᜢ‫( ܄‬Cook et al., 1995)Ǵՠࡕុ‫زࣴޑ‬٠ؒԖ ᡉҢ΋ठ‫ޑ܄‬ว౜ (Stephen V. Faraone et al., 2005; D et al., 2006; Purper-Ouakil et al., 2005)ǶԿ‫ܭ‬ӧ๮Γ‫ޑ‬௼ဂǴԖ‫زࣴঁٿ‬ϩձᡉҢ DAT1 ୷Ӣ‫ ޑ‬3´VNTR ‫ ޑ‬10-repeat (Chen et al., 2003) Ϸ 11-repeat (Qian et al., 2004) ᆶ ADHD ϐ໔‫ڀ‬ Ԗᡉ๱࣬ᜢ‫܄‬Ǵՠ‫ځ‬Ѭ‫زࣴঁٿ‬٠όЍ࡭೭ኬ‫࣬ޑ‬ᜢ‫( ܄‬Cheuk, Li, & Wong, 2006; Wang et al., 2008)Ƕ ΋٤Ӣનёૈёаှញӧ΢ॊ೭٤ࣴ‫่݀ز‬ϐ໔‫ޑ‬౦፦‫܄‬Ǵಃ΋Ǵၸѐࣴ ‫ز‬ᡉҢ ADHD ঁਢࢂցӕਔԖ‫ځ‬дᆒઓࣽӅੰ੯ੰ (comorbidity)Ǵ཮ቹៜ 16.

(24) ADHD ᆶ DAT1 ‫࣬ޑ‬ᜢ‫( ܄‬Zhou et al., 2008)ǴӢԜόӕ‫ ޑ‬ADHD ࣴ‫܌ز‬યΕ‫ޑ‬ ঁਢ‫ڀ‬Ԗόӕ‫ޑ‬Ӆੰᆒઓ੯ੰǴஒ཮ቹៜᆶ DAT1 ϐ໔‫࣬ޑ‬ᜢ‫܄‬ϩ‫݋‬ǹಃΒǴ җ‫ ܭ‬ADHD ҁ‫ޑي‬Ѧӧ߄౜ࠠ (phenotypes) ‫ڀ‬Ԗ࣬྽ε‫ޑ‬౦፦‫܄‬Ǵ‫ٯ‬ӵ ADHD ёаϩԋ‫ݙ‬ཀΚό‫ى‬٥ࠠ. (inattentive subtype) ǵ ၸ ୏ ᆶ ፂ ୏ ٥ ࠠ. (hyperactive-impulsive subtype)ǵаϷషӝࠠ (combined subtype)Ǵၸѐ‫زࣴޑ‬ᡉ Ңऩࢂஒ ADHD ບᘐᕭλጄൎԿࢌ΋੝‫ޑۓ‬٥ࠠǴஒёаቚуว౜ংᒧ୷Ӣ‫ޑ‬ ᐒ཮ (Genro et al., 2008; Waldman et al., 1998)Ƕ DAT1 ‫ ޑ‬3'VNTR ёૈᆶ‫ځ‬Ѭᎃ߈‫୷ޑ‬Ӣᡂ౦‫׎‬ԋೱᙹόѳᑽ (linkage disequilibriumǴLD)ǴӢԜӧ຾Չ ADHD ‫ޑ‬ϩη୷Ӣࣴ‫ز‬ਔǴᔈԵቾ DAT1 ୷ Ӣ΢‫ ޑ‬LD ่ᄬ (Greenwood et al., 2002)Ǵᗨฅၸѐ೚ӭࣴ‫ز‬೿ӧ௖૸ DAT1 ୷ Ӣᆶ ADHD ‫࣬ޑ‬ᜢ‫܄‬Ǵՠ‫ځ‬ύѝԖϿኧࣴ‫ز‬Ԗൔ֋᏾ঁ୷Ӣ‫ ޑ‬LD ่ᄬǴ΋໨ ่ӝΑΖঁ୯ৎ‫ޑ‬εೕኳࣴ‫ز‬ᡉҢǴADHD ঁਢ‫ ޑ‬DAT1 ୷Ӣӧ LD ่ᄬ΢Ԗ Ѥঁൂ঺ᡏ୔໔ (haplotype blocks)ǴԶӧቺ୯ (Friedel et al., 2007) ᆶЃՋ (Genro et al., 2008) ‫߾زࣴޑ‬ᡉҢΑΟঁൂ঺ᡏ୔໔ǶӧҺՖ΋ঁ੝‫ޑۓ‬௼ဂ္ य़Ǵँᡂǵ୷Ӣᅆ౽ (genetic drift)ǵаϷᅿ௼‫ޑ‬ᑼӝ฻Ӣન೿ёૈ཮ቹៜ LD ่ᄬǴӢԜӧόӕ‫ޑ‬௼ဂёૈ཮Ԗόӕ‫ ޑ‬LD ่ᄬǴਥᏵ‫ޕ܌ॺך‬Ǵၸѐ٠ؒ ԖҺՖ ADHD ‫୷ޑ‬Ӣࣴ‫ز‬௖૸ DAT1 ӧ๮Γ௼ဂ‫ ޑ‬LD ่ᄬǶ ନΑ΢ॊ‫܌‬ග‫ ޑډ‬3'VNTRǴϿኧ‫زࣴޑ‬ම࿶௖૸ DAT1 ୷Ӣ΢‫ځޑ‬Ѭൂਡ 㧿ለӭࠠ‫( ܄‬single nucleotide polymorphismǴSNP) ᆶ ADHD ϐ໔‫࣬ޑ‬ᜢ‫܄‬Ǵ ‫ٯ‬ӵ Brookes ฻Γමൔ֋ rs40184 ᆶ ADHD ϐ໔‫ڀ‬Ԗ࣬ᜢ‫( ܄‬Brookes et al., 2006)Ǵՠ Genro ฻Γ‫߾زࣴޑ‬όЍ࡭೭ኬ‫( ่݀ޑ‬Genro et al., 2008)ǴќѦǴ Friedel ฻Γ߾ൔ֋ rs27072 ᆶ ADHD ϐ໔‫ڀ‬Ԗ࣬ᜢ‫܄‬ǴԶӧ Gizer ฻Γ‫ޑ‬ meta-analysis ΨᡉҢ rs27072 ᆶ ADHD ϐ໔‫ޑ‬ᡉ๱࣬ᜢ‫܄‬Ƕ ӧ຾Չ ADHD ‫୷ޑ‬Ӣࣴ‫ز‬ਔᗋԖ΋ঁख़ा‫ޑ‬ӢનाуаԵቾǴӢࣁႽ ADHD ೭ኬ‫ޑ‬ᆒઓ੯ੰ΋‫ۓ‬όૈѝҔൂ΋୷Ӣᡂ౦ٰуаှញǴӢԜѝ᠘‫ൂۓ‬ ΋୷Ӣᡂ౦ѝૈග‫ߚٮ‬தԖज़‫ૻޑ‬৲Ǵՠࢂ DAT1 ୷Ӣς࿶ว౜Ԗ೚ӭ‫ޑ‬ᡂ 17.

(25) ౦Ǵ΋ঁख़ा‫ޑ‬ୢᚒࢂӵՖӧ೭ሶӭ‫ޑ‬ᡂ౦ύᒧ‫ڗ‬Ԗཀက‫ޑ‬኱૶ٰуа᠘‫ۓ‬Ǵ ٠຾΋‫؁‬ϩ‫݋‬೭٤኱૶ᆶ ADHD ϐ໔‫࣬ޑ‬ᜢ‫܄‬Ƕऩ‫ࢂॺך‬аᒿᐒ‫ޑ‬БԄٰᒧ‫ڗ‬ ा᠘‫୷ޑۓ‬Ӣᡂ౦Ǵ೭٠όࢂ΋ঁԖਏ‫ޑ‬Б‫ݤ‬Ǵ‫ॺך‬ሡाаࣽᏢᆶ‫س‬಍‫ޑ܄‬Б ‫ٰݤ‬ᒧ‫ڗ‬ёૈԖཀက‫୷ޑ‬Ӣᡂ౦Ǵၸѐ‫زࣴޑ‬ᡉҢ haplotype-tagging SNP ‫ޑ‬Б ‫ݤ‬ёаග‫ֹ׳ٮ‬᏾ΞԖਏ‫ޑ‬೼৩ٰ᠘‫୷ۓ‬Ӣ΢Ԗཀက‫ޑ‬ᡂ౦ (Kollins et al., 2008)ǴӢࣁ೭ᅿБ‫ݤ‬ёаᙖ๱ࣴ‫ ز‬LD ‫่ޑ‬ᄬٰ෧ϿόѸा‫୷ޑ‬Ӣ᠘‫ۓ‬Ǵ٠ቚ у‫׳‬ӭ‫୷ޑ‬Ӣ࣬ᜢ‫ૻ܄‬৲Ƕ ᏾ᡏٰᇥǴᗨฅ DAT1 ୷Ӣӧ ADHD ‫ੰޑ‬౛ᐒᙯ΢‫ת‬ᄽख़ा‫فޑ‬ՅǴՠӧ όӕ‫่݀زࣴޑ‬ϐ໔ϝฅӸӧܴᡉ‫ޑ‬ৡ౦‫܄‬Ǵ٠Ъ୷Ӣ‫ޑ‬բҔӧόӕ௼ဂϐ໔ ёૈԖόӕ‫ޑ‬ቹៜǴӢԜ‫ॺך‬ሡाჹ‫ܭ‬๮Γ௼ဂ DAT1 ୷Ӣ‫ ޑ‬LD ่ᄬуаࣴ ‫ز‬Ǵ຾΋‫؁‬ёаᙖҗ haplotype-tagging SNP ‫ޑ‬Б‫ݤ‬Ǵаߡӄय़‫܄‬Ӧ௖઩ DAT1 ୷Ӣӧ ADHD ‫ੰޑ‬౛ғ౛ᐒᙯǶ. 1.5.2 DAT1 ୷Ӣᆶ୺Չфૈምᛖϐ࣬ᜢ‫܄‬ җ‫ܭ‬΢ॊ୷Ӣ‫زࣴޑ‬ᡉҢ DAT1 ࢂ ADHD ‫ޑ‬ংᒧ୷ӢǴ‫ॺך‬຾΋‫׆؁‬ఈᡍ ᛾ DAT1 ࢂց཮೷ԋ ADHD ‫୺ޑ‬ՉфૈምᛖǶԖΠӈ൳Бय़‫ޑ‬᛾ᏵЍ࡭ DAT1 ୷Ӣᆶ୺ՉфૈࢂԖ࣬ᜢ‫ޑ܄‬Ǵಃ΋ǴDAT1 ୷Ӣকନ )knock-out) ‫ޑ‬ԴႵ೏ ว౜ӝ‫ٳ‬Ԗ୺Չфૈ‫ޑ‬લཞǴ‫ٯ‬ӵ‫ޜ‬໔πբ૶Ꮻ (spatial working memory) (B. Li et al., 2010) ‫ک‬ϸᔈ‫ڋ׭‬ምᛖ (Trinh et al., 2003)ǹಃΒǴmethylphenidate ᙖ๱‫׭‬ ‫ ڋ‬DAT Զගϲઓ࿶ँ᝻໔‫ޑ‬ӭЃữᐚࡋǴԶၸѐࣴ‫ز‬ว౜ methylphenidate ё а‫ׯ‬๓‫ ูٽ‬ADHD ஻‫୺ޑޣ‬Չфૈ (Vance et al., 2003)ǹಃΟǴၸѐࣴ‫ز‬ςᡉ Ң DAT1 ୷Ӣӧ଼ந‫୺ޑูٽ‬Չфૈ-‫ݙ‬ཀΚઓ࿶ᆛၡ (executive attention network) ‫ޑ‬ว৖‫ת‬ᄽख़ा‫ف‬Յ (Rueda et al., 2005)ǹಃѤǴቹႽ୷ӢᏢ‫زࣴޑ‬᛾ ჴӧ଼ந‫ڙ‬၂‫ ޑޣ‬DAT1 ୷Ӣᡂ౦ᆶπբ૶Ꮻ‫ޑ‬ઓ࿶ϸᔈ‫ڀ‬Ԗᡉ๱࣬ᜢ‫܄‬ (Stollstorff et al., 2010)Ƕᆕ΢‫܌‬ॊǴ௖઩ DAT1 ୷Ӣᆶ ADHD ஻‫୺ޑޣ‬Չфૈ 18.

(26) ምᛖϐ໔ᜢ߯‫ࢂزࣴޑ‬Μϩ‫ڀ‬Ԗሽॶ‫ޑ‬Ƕ ၸѐ೭Бय़‫زࣴޑ‬Ьा໣ύӧ DAT1 ୷Ӣ‫ ޑ‬3´VNTR ᆶ୺Չфૈምᛖϐ໔ ‫ޑ‬ᜢ߯ǴԶ೭٤ࣴ‫่݀ز‬۶ԜԖࡐε‫ޑ‬ৡ౦‫( ܄‬Barkley et al., 2006; Karama et al., 2008; Loo et al., 2008; Wohl et al., 2008)ǴKarama ฻Γว౜ DAT1 ୷Ӣ‫ ޑ‬3´VNTR ᆶ୺Չфૈύ‫ޑ‬πբ૶Ꮻᆶ‫ޜ‬໔ीฝԖᜢ (Karama et al., 2008)ǴCornish ฻Γ߾ ว౜Ǵऩ஻‫ޣ‬ӧ 3´VNTR ஥Ԗ 10-repeat ‫୷ޑ‬Ӣᡂ౦Ǵ߾ӕਔӝ‫ٳ‬Ԗၨৡ‫ޑ‬ᒧ᏷ ૶Ꮻᆶϸᔈ‫ૈڋ׭‬Κ (Cornish et al., 2005)ǴฅԶၸѐΨԖࣴ‫ز‬ൔ֋࣬ϸ‫่ޑ‬ ݀Ǵ‫ٯ‬ӵ Boonstra ฻Γว౜ ADHD ஻‫ޣ‬ऩࢂ஥Ԗ 10-repeat ‫୷ޑ‬Ӣᡂ౦ǴϸԶ ཮ԖКၨӳ‫୺ޑ‬Չфૈ߄౜ (Boonstra et al., 2008)ǴԜѦǴΨԖࣴ‫ࡰز‬р DAT1 ୷Ӣ‫ ޑ‬3' VNTR ᆶ ADHD ஻‫୺ޑޣ‬Չфૈምᛖϐ໔٠ค࣬ᜢ‫܄‬Ǵхࡴ‫ݙ‬ཀΚᙯ ඤբ཰ (Wisconsin Card Sorting Task) (Barkley et al., 2006)аϷћՅբ཰ (Stroop Color-Word Task) (Loo et al., 2008; Wohl et al., 2008)Ƕ೭٤ࣴ‫่݀ز‬۶Ԝϐ໔‫ޑ‬ ৡ౦ёૈᆶ൳Бय़‫ޑ‬ӢનԖᜢǴ‫ٯ‬ӵ ADHD ஻‫ޑޣ‬੝‫܌ک܄‬٬Ҕ‫ޑ‬ઓ࿶Ј౛Ꮲ ෳᡍ฻ǶԜѦǴёૈόࢂѝԖ DAT1 ୷Ӣ΢‫ࢌޑ‬΋ঁᡂ౦൩཮೷ԋ ADHD ஻‫ޣ‬ ‫୺ޑ‬ՉфૈምᛖǴԶࢂኧঁ୷Ӣᡂ౦уԋ‫ޑ‬ਏ݀ωᏤठΑ୺Չфૈ‫ޑ‬ምᛖǴӢ ԜѝԖ᠘‫ۓ‬΋ঁ੝‫୷ޑۓ‬Ӣࠠ (ӵ 3' VNTR) ٠ค‫ֹݤ‬᏾௖઩ DAT1 ୷Ӣӧ୺ Չфૈምᛖ‫ת܌‬ᄽ‫فޑ‬ՅǴΨ຾ԶౢғΑၸѐࣴ‫่݀ز‬۶Ԝϐ໔‫ޑ‬ৡ౦‫( ܄‬Mill et al., 2006)Ƕ ନΑ 3'VNTR ϐѦǴѝԖࡐϿኧ‫زࣴޑ‬ѐ௖૸ DAT1 ୷Ӣ‫ځޑ‬Ѭᡂ౦ᆶઓ࿶ Ј౛фૈϐ໔‫ޑ‬ᜢ߯ (Bellgrove et al., 2007; Kollins et al., 2008; Rommelse, et al., 2008)ǴBellgrove ฻Γว౜ӧ଼ந‫ڙ‬၂‫ޣ‬ύǴDAT1 ୷ӢಃΖঁϣᡉη (intron 8) ‫ ޑ‬3-repeat ᡂ౦ᆶ‫ޜ‬໔‫ݙ‬ཀΚ (spatial attention) Ԗᜢ (Bellgrove et al., 2007)Ǵӧ ΋ҽԏ໣Α 152 ঁ ADHD ৎ৥‫زࣴޑ‬ൔ֋ࡰрǴDAT1 ୷Ӣ΢‫ޑ‬Ѥঁ SNPsǴх ࡴ rs37020ǵrs464049 ǵrs409588ǵаϷ rs2042449 ฻Ǵᆶ࡭ុ‫ݙ‬ཀΚෳᡍ (Continuous Performance TaskǴCPT) ‫߄ޑ‬౜Ԗᜢ (Kollins et al., 2008)Ǵՠӧќ Ѧ΋ঁԏ໣Α 350 Տ ADHD ஻‫ޣ‬ᆶ 195 Տ҂วੰЋ‫ޑى‬ৎ௼ࣴ‫ز‬ύǴRommelse 19.

(27) ฻Γ߾ว౜ DAT1 ୷Ӣ΢‫ޑ‬Ϥঁᡂ౦Ǵхࡴ 3' VNTRǵintron 8ǵrs2550946ǵ rs11564750ǵrs3776513ǵаϷ rs40184 ฻Ǵᆶ୺Չфૈϐ໔٠คᡉ๱࣬ᜢ‫܄‬ (Rommelse et al., 2008)ǴӢԜ DAT1 ୷Ӣ΢ 3'VNTR аѦ‫ޑ‬ᡂ౦ᆶ୺Չфૈምᛖ ϐ໔ᜢ߯ϝԖࡑ຾΋‫زࣴ؁‬Ƕ ᏾ᡏԶ‫ق‬ǴᗨฅԖ٤ࣴ‫ز‬ว౜ DAT1 ୷Ӣᆶ ADHD ஻‫୺ޑޣ‬Չфૈምᛖϐ ໔‫ڀ‬Ԗ࣬ᜢ‫( ܄‬Cornish et al., 2005; Karama et al., 2008)Ǵՠ‫ځ‬д‫زࣴޑ‬٠όЍ࡭ ೭΋่݀ (Loo et al., 2008; Wohl et al., 2008)ǶӢԜჹ‫ ܭ‬DAT1 ୷Ӣӧ ADHD ୺ Չфૈምᛖ‫ת܌‬ᄽ‫فޑ‬ՅϝԖࡑ຾΋‫ޑ؁‬௖૸Ƕ. 1.6 ࣴ‫ز‬ୢᚒᆶଷᇥ ਥᏵ΢ॊ ADHD ઓ࿶ғ‫ނ‬Ꮲ‫ޑ‬Ў᝘ӣ៝Ǵ‫ॺך‬ගрΠӈ‫زࣴޑ‬ଷᇥǴ‫׆‬ఈ ૈ‫׳‬຾΋‫؁‬௖૸ ADHD ӧઓ࿶Ј౛Ꮲǵϣ߄౜ࠠǵᛰ‫ݯނ‬ᕍǵઓ࿶ቹႽᏢǵа Ϸ୷Ӣᒪ໺Ꮲ฻Бय़‫زࣴޑ‬᝼ᚒǴаයૈ‫׳‬మཱඓඝ ADHD ‫ੰޑ‬౛ᐒᙯǴ٠Ъ ‫׆‬ఈ҂ٰૈᔈҔ‫ ܭ‬ADHD ஻‫ޑޣ‬ᖏ‫׉‬ຑ՗ᆶ‫ݯ‬ᕍǶ. 1.6.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖ 1.6.1.1 ࣴ‫ز‬ୢᚒǺ(a)ADHD ஻‫ࢂޣ‬ցԖၨৡ‫୺ޑ‬Չфૈ (b)୺Չфૈᆶຎ᝺૶Ꮻࢂցࣁ ADHD ‫ޑ‬ϣ߄౜ࠠ 1.6.1.2 ࣴ‫ز‬ଷᇥǺ (a) җ‫ܭ‬ၸѐ‫زࣴޑ‬Ьाࢂ٬Ҕൂ΋‫ޑ‬ෳᡍٰຑ՗ ADHD ஻‫୺ޑޣ‬Չфૈም ᛖǴࣴ‫่݀ز‬۶Ԝϐ໔લЮКၨ‫܄‬ǴΨόܰඓඝ ADHD ஻‫ޣ‬᏾ᡏ‫୺ޑ‬ՉфૈǴ ӢԜ‫ॺך‬೛ी‫ޑ‬ჴᡍࢂ௦Ҕቆᐏઓ࿶Ј౛ෳᡍ (Cambridge Neuropsychological Test Automated BatteryΔCANTAB)Ǵ೭ࢂ΋ঁ‫ޜ‬໔ǵߚᇟ‫ޑق‬ႝတෳᡍǴх֖ 20.

(28) Αֹ᏾‫ޑ‬ઓ࿶Ј౛фૈෳᡍǴၸѐ‫زࣴޑ‬ς᛾ჴ CANTAB ӧ଼ந‫ڙ‬၂‫ޣ‬ύԖࡐ ӳ‫ߞޑ‬ਏࡋ (Luciana & Nelson, 1998)Ǵ٠ЪёаᔈҔ‫ܭ‬ຑ՗όӕ‫ޑ‬ᆒઓ੯ੰϐ ᇡ‫ޕ‬фૈǴхࡴኁᢠੱ (Purcell et al., 1997)ǵចᢠੱ (Sweeney et al., 2000)ǵᆒ ઓϩ຋ੱ (Levaux et al., 2007)ǵѨඵੱ (Egerhazi et al., 2007)ǵаϷΓ਱ምᛖੱ (Dolan & Park, 2002)Ƕჹ‫܌ॺךܭ‬ᜢ‫୺ޑݙ‬ՉфૈǴCANTAB ԖѤঁϩෳᡍࢂ Ҕٰຑ՗୺ՉфૈǴхࡴ SSPǵIEDǵSWMǵаϷ SOCǴӢԜ CANTAB ёа ֹ᏾Ӧຑ՗ ADHD ஻‫ޑޣ‬᏾ᡏ୺ՉфૈǶᗨฅၸѐՋБԖϿኧ‫زࣴޑ‬٬Ҕ CANTAB ٰຑ՗ ADHD ஻‫୺ޑޣ‬ՉфૈǴ٠Ъว౜஻‫ޣ‬ӧ SWM (Sinead M. Rhodes et al., 2004)ǵIED (Rhodes et al., 2005)ǵᆶ SOC (Kempton et al., 1999)฻ ϩෳᡍ߄౜ၨৡǴՠӧ๮Γ௼ဂ٠҂ම࿶٬Ҕ CANTAB ٰࣴ‫ ز‬ADHD ஻‫ޑޣ‬ ୺ՉфૈǶӢԜ‫ॺך‬ଷ೛Ǵᆶ଼ந‫ڙ‬၂‫࣬ޣ‬КǴߙϿԃ ADHD ஻‫ޑޣ‬ӧ SSPǵ IEDǵSWMǵаϷ SOC ฻ CANTAB ‫୺ޑ‬Չфૈϩෳᡍ‫ޑ‬ϩኧ֡ၨեǶ. (b) ၸѐᗨฅԖࣴ‫ز‬௖૸ ADHD ஻‫ޣ‬ϐ҂วੰ‫ޑ‬ᒃឦϐ୺ՉфૈምᛖǴՠࣴ‫ز‬ ่݀۶Ԝϐ໔Ԗࡐε‫ޑ‬ৡ౦‫( ܄‬Asarnow et al., 2002; Murphy & Barkley, 1996; D. Slaats-Willemse et al., 2003; D. I. Slaats-Willemse et al., 2007)Ǵ೭ёૈࢂҗ‫ܭ‬ၸѐ ‫زࣴޑ‬ኬҁό୼εǴ٠Ъѝ٬Ҕൂ΋π‫ٰڀ‬ຑ՗୺ՉфૈǴаठค‫ݤ‬Ԗ‫ޑ୼ى‬ ಍ीᔠ‫ۓ‬Κٰ௖઩ ADHD ஻‫ޣ‬ϐ҂วੰᒃឦ‫ޑ‬᏾ᡏ୺ՉфૈǶќѦǴ߻ॊ‫ޑ‬ CANTAB ࢂ΋ঁ‫ڀ‬Ԗଯࡋ௵ག‫܄‬ᆶᆒዴ‫ޑ܄‬ઓ࿶Ј౛ຑ՗π‫ڀ‬Ǵёаୀෳр ADHD ஻‫ޣ‬ϐ҂วੰᒃឦಒ༾‫( ޑ‬subtle) ୺ՉфૈምᛖǴՠ CANTAB ၸѐ٠ ҂ම٬Ҕ‫ܭ‬ຑ՗ ADHD ஻‫ޣ‬ϐ҂วੰᒃឦǶӢԜ‫ॺך‬Ⴃीԏ໣ΟಔঁਢǴх֖ ADHD ஻‫ޣ‬ǵADHD ஻‫ޣ‬ϐ҂วੰЋ‫ى‬ǵаϷ଼ந‫ڙ‬၂‫ޣ‬Ǵ٠Ъ٬Ҕ CANTAB ‫ ޑ‬SSPǵIEDǵSWMǵаϷ SOC ฻ϩෳᡍٰຑ՗Οಔঁਢ‫୺ޑ‬ՉфૈǴ‫ॺך‬ଷ ೛ ADHD ஻‫ޣ‬ஒ཮Ԗനᝄख़‫୺ޑ‬ՉфૈምᛖǴԶ ADHD ஻‫ޣ‬ϐ҂วੰЋ‫ޑى‬ ୺Չфૈ߄౜ஒ཮Տ‫ ܭ‬ADHD ஻‫ޣ‬ᆶ଼ந‫ڙ‬၂‫ޣ‬ϐ໔Ƕ 21.

(29) ନΑ୺ՉфૈϐѦǴ౜Ԗ‫زࣴޑ‬ςᡉҢ ADHD ஻‫཮ޣ‬ӝ‫ٳ‬ຎ᝺૶Ꮻ‫ޑ‬ም ᛖǴՠၸѐ٠คҺՖࣴ‫ز‬௖૸ ADHD ஻‫ޣ‬ϐ҂วੰᒃឦ‫ޑ‬ຎ᝺૶ᏫфૈǴӢԜ ຎ᝺૶Ꮻࢂցёբࣁ ADHD ‫ޑ‬ϣ߄౜ࠠϝԖࡑ຾΋‫؁‬ᡍ᛾Ƕ‫ॺך‬٬Ҕ CANTAB ‫ޑ‬ຎ᝺૶ᏫϩෳᡍǴх֖‫ۯ‬ᒨኬҁଛჹ (Delayed Matching to SampleΔDMS)ǵ ‫ޜ‬໔ᒣᇡ૶Ꮻ (Spatial Recognition MemoryΔSRM)ǵଛჹ࣬ᜢᏢಞ (Paired Associates LearningΔPAL)ǵаϷ‫׎‬ᄊᒣᇡ૶Ꮻ (Pattern Recognition MemoryΔ PRM)Ǵٰຑ՗߻ॊΟಔঁਢ‫ޑ‬ຎ᝺૶ᏫǴ‫ॺך‬ଷ೛ ADHD ஻‫ޣ‬ஒ཮Ԗനᝄख़ ‫ޑ‬ຎ᝺૶ᏫምᛖǴԶ ADHD ஻‫ޣ‬ϐ҂วੰЋ‫ޑى‬ຎ᝺૶Ꮻфૈ߄౜ஒ཮Տ‫ܭ‬ ADHD ஻‫ޣ‬ᆶ଼ந‫ڙ‬၂‫ޣ‬ϐ໔Ƕ. 1.6.2 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ϣ߄౜ࠠᆶᛰ‫ݯނ‬ᕍ 1.6.2.1 ࣴ‫ز‬ୢᚒǺatomoxetine ёց‫ׯ‬๓ ADHD ஻‫୺ޑޣ‬Չфૈᆶ ຎ᝺૶Ꮻምᛖ 1.6.2.2 ࣴ‫ز‬ଷᇥǺ Ў᝘ӣ៝ว౜୺Չфૈࢂ ADHD ‫ޑ‬ϣ߄౜ࠠǴՠҗ‫ܭ‬ၸѐѝԖ΋ঁλࠠ‫ޑ‬ Ӄ០ࣴ‫ز‬௖૸ atomoxetine ࢂցૈ‫ׯ‬๓‫ ูٽ‬ADHD ஻‫୺ޑޣ‬Չфૈምᛖ (Barton et al., 2005)ǴӢԜϝԖࡑ຾΋‫زࣴ؁‬аຑ՗ atomoxetine ჹ‫ ูٽܭ‬ADHD ஻‫ޣ‬ϐ ୺Չфૈ‫ޑ‬ቹៜǶ‫ॺך‬ஒԏ໣‫׳‬ӭ‫ ูٽޑ‬ADHD ஻‫ޣ‬Ǵ٠Ъ٬Ҕ CANTAB ‫ޑ‬ SSPǵIEDǵSWMǵаϷ SOC ฻ϩෳᡍǴٰ௖઩ӧߏය٬Ҕ atomoxetine ϐࡕǴ ‫ ูٽ‬ADHD ஻‫୺ޑޣ‬ՉфૈࢂցԖ຾‫؁‬Ƕ‫ॺך‬ଷ೛Ǵatomoxetine όѝૈ‫ׯ‬๓ ADHD ‫ރੱޑ‬ǴΨૈ‫ׯ‬๓஻‫୺ޑޣ‬ՉфૈምᛖǶ ନΑ୺ՉфૈምᛖϐѦǴ‫زࣴޑॺך‬Ψว౜ ADHD ஻‫཮ޣ‬ӝ‫ٳ‬Ԗຎ᝺૶Ꮻ ምᛖǴ٠Ъຎ᝺૶Ꮻёа଺ࣁ ADHD ‫ޑ‬ϣ߄౜ࠠǴӢԜ‫ॺך‬٬Ҕ CANTAB ‫ޑ‬ SRM ᆶ PRM ฻ϩෳᡍǴٰ௖઩ӧߏය٬Ҕ atomoxetine ϐࡕǴ‫ ูٽ‬ADHD ஻ 22.

(30) ‫ޑޣ‬ຎ᝺૶ᏫфૈࢂցԖ຾‫؁‬Ƕ‫ॺך‬ଷ೛Ǵatomoxetine ૈ‫ׯ‬๓஻‫ޑޣ‬ຎ᝺૶Ꮻ ምᛖǶ. 1.6.3 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୺ޑ‬Չфૈምᛖᆶઓ࿶ቹႽᏢ 1.6.3.1 ࣴ‫ز‬ୢᚒǺᚐယદ‫ރ‬ᡏઓ࿶ၡ৩ϐֹ᏾‫ࢂ܄‬ցᆶ ADHD ϐੱ ‫୺کރ‬ՉфૈምᛖԖ࣬ᜢ‫܄‬ 1.6.3.2 ࣴ‫ز‬ଷᇥǺ ᗨฅЎ᝘ӣ៝ύςԖ೚ӭࣴ‫ز‬٬Ҕ DTI ‫ޑ‬Б‫ٰݤ‬௖૸ ADHD ஻‫ޑޣ‬ᚐယદ ‫ރ‬ᡏϐқ፦ಒ༾่ᄬ‫ֹޑ‬᏾‫܄‬ǴՠҞ߻ϝ҂Ԗࣴ‫ز‬٬Ҕᘉණᓎ᛼೷ቹ (diffusion spectrum imagingǴDSI) ‫ޑ‬Б‫ زٰࣴݤ‬ADHD ஻‫ޑޣ‬ᚐယદ‫ރ‬ᡏǶ࣬ჹ‫ܭ‬໺಍ ‫ ޑ‬DTIǴ DSI ૈ୼ ӧ တ೽‫ޑ‬ઓ࿶ ᖄ่຾Չ ‫ֹ׳‬᏾‫ޑ‬ᘉණ‫܄‬ຑ՗ (diffusion measurement)Ǵаठ DSI ૈ୼Ԗ‫׳‬ӳ‫ࡋفޑ‬ှ‫( ࡋ݋‬angular resolution) ٰೀ౛ ઓ࿶ᠼᆢҬΰ‫ޑ‬ୢᚒǴԶҞ߻ DSI ς࿶೏᛾ჴёаԖਏӦҔٰख़ࡌ೚ӭᆒઓ੯ ੰ‫ޑ‬တ೽ઓ࿶ၡ৩Ǵхࡴமॐੱ (Chiu et al., 2011)ǵଚᆒ٩ᒘ (I. C. Liu et al., 2010)ǵаϷԾഈੱ (Lo et al., 2011)฻Ƕၸѐ‫زࣴޑ‬ᡉҢӧઓ࿶ᠼᆢҬΰ‫ޑ‬တ೽ ୔ୱǴDTI ஒ཮ख़ࡌᒱᇤ‫ޑ‬ઓ࿶ᠼᆢၡ৩ (false fiber pathways) (Wedeen et al., 2008)Ǵ៝ӜࡘကǴᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ၡ৩ࢂᖄᛠᚐယ‫ډ‬દ‫ރ‬ᡏϐ໔‫ޑ‬ઓ࿶ᠼ ᆢǴӧઓ࿶ှওᏢ΢೭చၡ৩཮ᆶ೚ӭ‫ځ‬Ѭ‫ޑ‬ઓ࿶ᠼᆢ‫״‬ҬΰǴӢԜऩ٬Ҕ໺ ಍‫ ޑ‬DTI ٰख़ࡌᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ၡ৩Ǵ೭ஒ཮ࢂߚத֚ᜤ‫ޑ‬πբǴԶЪ໪ा ࡐӭ‫ޑ‬Ћ୏ᏹբ (manual editing) аѐନᒱᇤ‫ޑ‬ઓ࿶ၡ৩Ƕ࣬ჹӦǴऩ٬Ҕ DSI ٰख़ࡌᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ၡ৩ǴନΑёаԖਏӦᗉխઓ࿶ᠼᆢ‫״‬Ҭΰ‫ޑ‬ୢᚒǴ ԶЪᗋёаஒᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ၡ৩բ‫׳‬ᆒಒ‫ޑ‬೽Տ୔ϩ (segmentation)Ǵٰ௖ ૸Ԝઓ࿶ၡ৩ᆶ ADHD ϐ໔‫ڀ׳‬੝౦‫( ܄‬specific) ‫ޑ‬ᜢ߯ǶԜѦǴ‫׳ॺך‬຾΋ ‫؁‬ѐϩ‫ ݋‬ADHD ‫୺ޑ‬Չфૈምᛖᆶᚐယદ‫ރ‬ᡏ‫ޑ‬ઓ࿶ၡ৩ϐ໔‫ޑ‬ᜢ߯Ƕ‫ॺך‬ճ 23.

(31) Ҕ DSI ‫ ޑ‬Б ‫ ݤ‬ஒ ᚐ ယ દ ‫ ރ‬ᡏ ‫ ޑ‬ઓ ࿶ ၡ ৩ ୔ ϩ ԋ Ѥ ঁ ೽ Տ Ǵ х ࡴ caudate nucleus±DLPFC (dorsolateral)ǵcaudate nucleus±MPFC (medial prefrontal)ǵcaudate nucleus±OFC (orbitofrontal)ǵаϷ caudate nucleus±VLPFC (ventrolateral)Ǵ٠ෳ ໆ ADHD ஻‫ޣ‬ᆶ଼ந‫ڙ‬၂‫ޑޣ‬΋૓‫܄‬ϐ೽ϩ౦ӛ‫( ܄‬generalized fractional anisotropyΔGFA)Ǵ‫ॺך‬ଷ೛Ǵᆶ଼ந‫ڙ‬၂‫࣬ޣ‬КǴADHD ஻‫ޑޣ‬೭Ѥచઓ࿶ ၡ৩ϐ GFA ၨեǴ٠Ъ೭Ѥచઓ࿶ၡ৩‫ ޑ‬GFA ཮ᆶ ADHD ‫୺ޑ‬Չфૈምᛖϐ ໔‫ڀ‬Ԗᡉ๱‫࣬ޑ‬ᜢ‫܄‬Ƕ. 1.6.4 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫୷ޑ‬Ӣᒪ໺Ꮲ 1.6.4.1 ࣴ‫ز‬ୢᚒǺ(a) DAT1 ୷Ӣࢂցᆶ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ࣬ᜢ (b) DAT1 ୷Ӣࢂցᆶ୺Չфૈምᛖ࣬ᜢ 1.6.4.2 ࣴ‫ز‬ଷᇥǺ (a) ᗨฅ DAT1 ୷Ӣӧ ADHD ‫ੰޑ‬౛ғ౛ᐒᙯύ‫ת‬ᄽख़ा‫فޑ‬ՅǴՠၸѐ‫ࣴޑ‬ ‫่݀ز‬ϐ໔ϝӸӧࡐε‫ޑ‬ৡ౦‫܄‬Ǵ੝ձࢂӧ๮Γ‫ޑ‬௼ဂၸѐѝଞჹ DAT1 ୷Ӣ ΢‫ࢌޑ‬൳ঁᡂ౦଺ၸ௖઩Ǵ٠҂ଞჹ DAT1 ୷Ӣ଺ၸ᏾ᡏӄय़‫زࣴޑ‬ǴӢԜ DAT1 ୷Ӣӧ๮Γ௼ဂ‫ ޑ‬ADHD ஻‫ת܌ޣ‬ᄽ‫فޑ‬ՅϝԖࡑዴᇡ (Cheuk et al., 2006; Wang et al., 2008)Ƕ‫زࣴޑॺך‬ஒ௦Ҕ haplotype-tagging SNP ‫ޑ‬Б‫ݤ‬Ǵٰ ֹ᏾ຑ՗ DAT1 ୷Ӣᆶ ADHD ϐ໔‫ޑ‬ᜢ߯ǴԶЪ‫ॺך‬Ψ཮ஒ ADHD ஻‫୔ޣ‬ϩ ԋόӕ‫ޑ‬٥ࠠ (subtype)Ǵٰ௖૸ DAT1 ୷Ӣᆶόӕ ADHD ٥ࠠ‫׳ޑ‬੝౦‫ޑ‬ᜢ ߯Ƕ‫ॺך‬ଷ೛ǴDAT1 ୷Ӣ΢‫ޑ‬ᡂ౦όՠᆶ ADHD Ԗ࣬ᜢ‫܄‬ǴԶЪᆶ ADHD ‫ޑ‬ ੱ‫ރ‬ᆶ٥ࠠԖ࣬ᜢ‫܄‬Ƕ. (b) 24.

(32) ᏾ᡏԶ‫ق‬Ǵᗨฅၸѐ΋٤ࣴ‫ز‬٠҂ว౜ DAT1 ୷Ӣᆶ ADHD ஻‫୺ޑޣ‬Չф ૈምᛖԖ࣬ᜢ‫( ܄‬Barkley et al., 2006; Loo et al., 2008; Rommelse et al., 2008; Wohl et al., 2008)ǴՠΨԖࣴ‫ز‬᛾ჴ DAT1 ୷Ӣᆶ୺Չфૈύ‫ޜޑ‬໔ीฝ (the tower of London) ᆶπբ૶Ꮻ (working memory) Ԗ࣬ᜢ‫( ܄‬Karama et al., 2008)ǴӢԜ DAT1 ୷Ӣᆶ ADHD ஻‫୺ޑޣ‬Չфૈምᛖϐ໔‫ޑ‬ᜢ߯ϝԖࡑ຾΋ ‫ޑ؁‬௖૸ǶԶ‫ॺך‬ၸѐ‫زࣴޑ‬ς᛾ჴ DAT1 ୷Ӣࢂ ADHD ‫ޑ‬ংᒧ୷Ӣ (Shang et al., 2011)ǴԶЪӧઓ࿶Ј౛Ꮲࣴ‫ز‬ύ‫ॺך‬Ψ᛾ჴΑ٬Ҕ CANTAB ٰຑ՗‫୺ޑ‬Չ фૈምᛖǴх֖ SSPǵSWMǵIEDǵаϷ SOC ฻Бय़Ǵёаբࣁ ADHD ‫ޑ‬ϣ ߄౜ࠠ (Gau & Shang, 2010a)Ǵ‫ځ‬ύΞа SWM ‫ޑ‬ਏᔈॶ (effect size)ࣁനεǴ ӢԜ‫ॺך‬ӧ೭΋ঁৎ௼୷Ӣࣴ‫ز‬ύஒ຾΋‫؁‬௖઩ DAT1 ୷Ӣᆶ ADHD ஻‫୺ޑޣ‬ Չфૈምᛖϐ໔‫ޑ‬ᜢ߯ǶਥᏵ‫ॺך‬ၸѐ‫ޑ‬ϣ߄౜ࠠࣴ‫ز‬Ǵ‫ॺך‬ଷ೛ǴDAT1 ୷ Ӣᆶ ADHD ஻‫୺ޑޣ‬ՉфૈምᛖǴ੝ձࢂ SWM ‫߄ޑ‬౜Ǵ۶Ԝϐ໔཮Ԗᡉ๱‫ޑ‬ ࣬ᜢ‫܄‬Ƕ. 25.

(33) 2. ࣴ‫ز‬Б‫ݤ‬ᆶ‫׷‬਑ (Materials and methods). 2.1 ‫ݙ‬ཀΚό‫ى‬ၸ୏ੱ‫ޑ‬ઓ࿶ᇡ‫ޕ‬фૈምᛖ 2.1.1 ઓ࿶ᇡ‫ޕ‬фૈምᛖ 2.1.1.1 ‫ڙ‬၂‫ޣ‬Ϸ‫؁‬ᡯ ҁࣴ‫ز‬ԏ໣Α 53 Տ 11 ‫ ډ‬16 ྃ‫ߙޑ‬Ͽԃ ADHD ஻‫ޣ‬Ǵ‫ځ‬ύ 40 Տࣁ‫܄ت‬Ǵ 13 Տࣁζ‫܄‬Ǵѳ֡ԃសࣁ 12.7±1.4 ྃǴ೭٤஻‫ޣ‬ၸѐр౜ܴᡉ ADHD ੱ‫ޑރ‬ѳ ֡ԃសࣁ 4.8±1.7 ྃǴಃ΋ԛӧᖏ‫׉‬΢೏ບᘐࣁ ADHD ‫ޑ‬ѳ֡ԃសࣁ 7.6±2.9 ྃǴ ќѦ‫ॺך‬Ψவ஻‫ޑޣ‬ӕ΋Ꮲ୔ԏ໣Α 53 Տ଼ந‫ڙ‬၂‫ޣ‬բࣁჹྣಔǴჹྣಔ‫܄ޑ‬ ձǵԃសǵඵ୘ǵР҆‫ޑ‬௲‫ػ‬ำࡋ֡ςᆶ ADHD ಔଛჹǴፎ‫ ߄ـ‬1Ƕ ҆ᒃᆶঁਢ֡ϩձௗ‫ڙ‬ᆒઓࣽບᘐ‫཮܄‬ፋπ‫ ڀ‬the Kiddie epidemiologic version of the Schedule for Affective Disorders and Schizophrenia (K-SADS-E) ‫ޑ‬ຑ ՗Ǵаዴҥ‫ځ‬ບᘐǶӧ 53 Տ ADHD ஻‫ޣ‬ύǴԖ 29 (54.7%) Տບᘐࣁషӝ٥ࠠǴ 17 (32.1%) Տࣁ‫ݙ‬ཀΚό‫ى‬٥ࠠǴ7 (13.2%) Տࣁၸ୏ፂ୏٥ࠠǶ‫ڙ‬၂‫֡ޣ‬ௗ‫ڙ‬ CANTAB ‫ޑ‬ઓ࿶Ј౛ෳᡍǴԜѦǴ‫ॺך‬ΨᒧҔඵΚෳᡍύ digit span ٰຑ՗ঁਢ ‫ݙុ࡭ޑ‬ཀΚ‫ک‬ᇟ‫ق‬πբ૶ᏫǶऩࢂҞ߻҅ӧܺҔ ADHD ᛰ‫ޑނ‬஻‫ޣ‬Ǵ߾ӧௗ ‫ڙ‬ෳᡍϐ߻ԿϿଶЗܺҔᛰ‫ ނ‬24 λਔа΢Ƕԏਢ‫ޑ‬௨ନచҹӵΠǺԖᝄख़‫ي‬ᡏ ੯ੰӵЈՈᆅ੯ੰǵӄඵ୘λ‫ ܭ‬80ǵᚈཱུ‫܄‬௃ག‫܄‬੯ੰੰўǵ‫ނ‬፦ᔲҔੰўǵ ᆒઓϩ຋ੱੰўǵቶ‫܄ݱ‬ว৖ምᛖੱੰўǵ‫ޣ܈‬ᡜ⻯ੰў฻Ƕ. 2.1.1.2 ઓ࿶Ј౛ෳᡍǺCABTAB ઓ࿶Ј౛ෳᡍࢂҗᖏ‫׉‬Ј౛ৣਥᏵ CANTAB ‫ޑ‬኱ྗࢬำуаࡼෳǴӦᗺӧ ѠεᙴଣᆒઓᙴᏢ೽‫ޑ‬ઓ࿶Ј౛ᔠࢗ࠻Ǵෳᡍ‫ޑ‬ਔ໔εऊࣁ 90 ϩដǴ‫ॺך‬ᒧҔ CANTAB ‫ޑ‬Ѥঁϩෳᡍаຑ՗‫ڙ‬၂‫୺ޑޣ‬ՉфૈǴаΠϩձϟಏ೭ѤঁϩෳᡍǺ 26.

(34) Spatial Span (SSP). SSP ࢂຑ՗‫ڙ‬၂‫ޜޑޣ‬໔อය૶ᏫǴ΋໒‫ۈ‬ႝတᑻჿ΢཮ р౜ኧঁ‫ۓڰ‬Տ࿼‫ޑ‬қՅБ਱Ǵϐࡕ‫ঁ؂‬Б਱཮٩ྣႣ೛‫ޑ‬໩‫ׇ‬Ǵ΋ঁБ਱ௗ๱ ΋ঁБ਱ᙯᡂᚑՅǴ‫ڙ‬၂‫ޣ‬Ѹ໪ਥᏵӃ߻Б਱ᙯᡂᚑՅ‫ޑ‬໩‫ׇٰ‬᝻࿘ᑻჿ΢‫୔ޑ‬ ୱǴෳᡍҗ‫ঁٿ‬Б਱໒‫ۈ‬ǴനӭԿΐঁБ਱ǶനࡕԖΟঁୖኧж߄‫ڙ‬၂‫߄ޑޣ‬౜Ǻ (1) span lengthǺૈ೏ԋфӣᏫଆ‫ޑ‬നߏ໩‫ׇ‬ǹ(2) total errorsǺᒱᇤ೏ᒧ᏷‫ޑ‬Б਱ ᕴኧǹ(3) total usage errorsǺ‫ڙ‬၂‫ޣ‬ᒧ᏷΋ঁόӧ೏ӣᏫ໩‫ޑׇ‬Б਱ϐԛኧǶ Spatial Working Memory (SWM). SWM ࢂຑ՗‫ڙ‬၂‫ޜޑޣ‬໔πբ૶ᏫǴ‫ڙ‬၂ ‫ޣ‬೏ा‫؃‬ӧᑻჿ΢೚ӭ‫ޑ‬Б਱㚊൨‫פ‬ᗦᙒӧ‫ځ‬ύᙔՅ‫ޑ‬Б༧Ǵ‫ڙ‬၂‫ޣ‬ӧว౜ᙔՅ Б༧ࡕǴѸ໪ҔЋࡰ᝻࿘ᑻჿஒБ༧౽ԿᑻჿѓБೀǴԶ‫؂‬ԛෳᡍύ΋ѿБ਱ύ ‫ޑ‬ᙔՅБ༧೏‫ࡕډפ‬Ǵ೭ঁБ਱൩ό཮ӆр౜ҺՖᙔՅБ༧ǴӢԜ‫ڙ‬၂‫ޣ‬Ѹ໪΋ ᜐ൨‫פ‬ཥ‫ޑ‬ᙔՅБ༧Ǵ΋ᜐ‫૶آ‬Ӄ߻ςр౜ᙔՅБ༧‫ޑ‬Б਱ǶനࡕԖ‫ୖঁٿ‬ኧж ߄‫ڙ‬၂‫߄ޑޣ‬౜Ǻ(1) strategy utilizationǺவཥ‫ޑ‬Б਱໒‫ۈ‬ཛྷ൨‫ޑ‬ԛኧǹ(2) Errors in total and three different levels of difficultyǺᒱᇤཛྷ൨‫ޑ‬ᕴԛኧǴаϷӧΟঁόӕ ᜤࡋ(4-, 6-, and 8-box problems)‫ޑ‬ᒱᇤཛྷ൨ԛኧǶ Intra-dimensional/Extra-dimensional Shifts (IED). IED ࢂຑ՗‫ڙ‬၂‫ݙޑޣ‬ཀΚ ᙯඤૈΚǴႝတᑻჿ΢཮р౜‫ٿ‬ᅿόӕ੝፦‫ޑ‬Ҟ኱‫ނ‬Ǵ΋ঁࢂጕచǴќѦ΋ঁ߾ ࢂ‫ރ׎‬Ǵ೭ঁෳᡍ٩ྣᜤࡋᕴӅԖ 9 ঁ໘ࢤǴ΋໒‫ڙۈ‬၂‫ޣ‬Ѹ໪ਥᏵ‫ޑރ׎‬੝ᗺ ٰ‫פ‬р҅ዴ‫ޑ‬ೕ߾Ǵ೭ࢂ‫܌‬ᒏ‫ޑ‬ӛࡋϣᙯඤ(intradimensional shiftsΔIDS)ǴௗΠ ٰ‫ڙ‬၂‫ޣ‬Ѹ໪ᙯ౽‫ݙ‬ཀΚԿጕచ‫ޑ‬੝ᗺٰ‫פ‬р҅ዴ‫ޑ‬ೕ߾Ǵ೭ࢂ‫܌‬ᒏ‫ޑ‬ӛࡋѦᙯ ඤ (extradimensional shiftsΔEDS)Ǵӧ᏾ঁෳᡍၸำύ‫ڙ‬၂‫ޣ‬Ѹ໪ᙖ๱၂ᇤᏢಞ (trial and error) а‫פ‬р҅ዴ‫ޑ‬ೕ߾ǴԶႝတ΋ѿୀෳ‫ډ‬ೱុ 6 ԛ‫ڙ‬၂‫҅ޣ‬ዴ‫ޑ‬ϸ ᔈϐࡕǴೕ߾ஒ཮Ծ୏ᙯඤǶനࡕԖѤঁୖኧж߄‫ڙ‬၂‫߄ޑޣ‬౜Ǻ(1)ԋфֹԋ ‫ ޑ‬stages ኧҞǹ(2)ࣁΑֹԋ stages ‫ޑ଺܌‬჋၂ϐᕴኧǹ(3)ӧ EDS ϐ߻‫ޑ‬ᒱᇤᕴ ኧǹ(4)ӧ EDS ය໔‫ޑ‬ᒱᇤᕴኧǶ Stocking of Cambridge (SOC). SOC ࢂຑ՗‫ڙ‬၂‫ޜޑޣ‬໔ीฝૈΚǴ΋໒‫ۈ‬ᑻ ჿ΢཮Ԗ‫ٿ‬ӈ‫ޑ‬ՅౚǴ‫؂‬΋ӈԖΟঁՅౚǴ΢ӈՅౚ‫ޑ‬௨ӈБԄࢂΠӈՅౚ‫ޑ‬ኳ 27.

(35) ݈ (template)Ǵӧ౽୏Յౚϐ߻‫ڙ‬၂‫ޣ‬Ѹ໪ӃӧЈύೕฝǴаߡૈҔനϿ‫ޑ‬౽୏ ԛኧஒΠӈՅౚ௨ӈԋ΢ӈՅౚ‫ޑ‬໩‫ׇ‬Ƕ΢ӈՅౚ‫ޑ‬௨ӈБԄ٣Ӄ࿶ၸ೛ीǴਥ Ᏽᜤࡋ‫ޑ‬όӕԖ 2ǵ3ǵ4ǵ‫ ܈‬5 ԛ‫ޑ‬നϿ౽୏ԛኧ (minimum number of moves)Ƕ നࡕԖѤঁୖኧж߄‫ڙ‬၂‫߄ޑޣ‬౜Ǻ(1)ӧόӕᜤࡋ‫ޑ‬౽୏ԛኧύԋфှ،‫ޑ‬ୢ ᚒኧҞǹ(2)ѳ֡౽୏ԛኧǹ(3)வ‫ڙ‬၂‫ࡘޣ‬ԵӵՖှ،ୢᚒ‫ډ‬໒‫ۈ‬౽୏ಃ΋ঁՅ ౚ‫ޑ‬ਔ໔ǹ(4)வ‫ڙ‬၂‫ޣ‬໒‫ۈ‬౽୏ಃ΋ঁՅౚ‫ֹډ‬ԋୢᚒ‫ޑ‬ਔ໔Ƕ. 2.1.1.3 ಍ीϩ‫݋‬ ඔॊ‫܄‬಍ी‫ޑ‬೽ϩаኧҞ‫ک‬ԭϩКٰᡉҢᜪձᡂ໨Ǵаѳ֡ॶ‫ک‬኱ྗৡٰᡉ Ңೱុᡂ໨ǶࣁΑ຾Չଛჹ‫ٯੰޑ‬ჹྣࣴ‫ز‬Ǵ‫ॺך‬ҔచҹԄ‫ޑ‬ᡄᒠӣᘜϩ‫݋‬аК ၨ஻‫ޣ‬ಔᆶჹྣಔ‫ޑ‬ᆒઓ੯ੰК౗Ǵ٠Ъа಍ी೬ᡏ SAS 9.1 (SAS Institute Inc., Cary, NC, USA) ‫ ޑ‬Proc Glimmix ࡰзٰीᆉയᆉК (odds ratioΔOR) ‫ ک‬95%‫ޑ‬ ߞᒘ୔໔Ƕჹ‫ܭ‬ೱុᡂ໨Ǵ‫ॺך‬٬Ҕጕ‫܄‬ӭ໘ቫኳԄ (linear multi-level model) ٰКၨ‫ٿ‬ಔ‫ ޑ‬CANTAB Ѥঁϩෳᡍ‫ޑ‬ϩኧǴჹ‫ٗܭ‬٤Ԗόӕᜤܰำࡋ‫ޑ‬ෳᡍ (SWM ‫ ک‬SOC)Ǵ‫ॺך‬ӧᔠᡍಔձᆶᜤܰࡋ‫ޑ‬ҬϕբҔਔ཮ਠ҅ӧӕ΋ঁঁਢ‫܌‬ ຾Չ‫ޑ‬ख़ፄෳໆǴAlpha ॶ೛‫ۓ‬ӧ 0.05Ǵ‫ॺך‬٬Ҕ &RKHQ¶Vd ‫ޑ‬Б‫ݤ‬ीᆉਏᔈॶ (effect size)Ǵऩ &RKHQ¶Vd ε‫ ܭ‬0.3 ՠλ‫ ܭ‬0.5 ߾ࣁλ (small) ‫ޑ‬ਏᔈॶǴऩ &RKHQ¶Vd ε‫ ܭ‬0.5 ՠλ‫ ܭ‬0.8 ߾ࣁύ฻ (medium) ‫ޑ‬ਏᔈॶǴऩ &RKHQ¶Vd ε‫ܭ‬ 0.8 а΢߾ࣁε (large) ‫ޑ‬ਏᔈॶǶ. 2.1.2 ઓ࿶ᇡ‫ޕ‬ϣ߄౜ࠠ 2.1.2.1 ‫ڙ‬၂‫ޣ‬Ϸ‫؁‬ᡯ ҁࣴ‫ز‬ԏ໣Α 279 Տ 8 ‫ ډ‬16 ྃ‫ ูٽޑ‬ADHD ஻‫ޣ‬Ǵ‫ځ‬ύ 85.7%ࣁ‫܄ت‬Ǵѳ ֡ԃសࣁ 12.5±1.6 ྃǴ೭٤஻‫ޣ‬ၸѐр౜ܴᡉ ADHD ੱ‫ޑރ‬ѳ֡ԃសࣁ 4.2±1.6 ྃǴಃ΋ԛӧᖏ‫׉‬΢೏ບᘐࣁ ADHD ‫ޑ‬ѳ֡ԃសࣁ 6.7±2.9 ྃǴӕਔ‫ॺך‬ԏ໣ 28.

(36) ADHD ஻‫ޣ‬҂วੰϐЋ‫ى‬Ӆ 108 ΓǴѳ֡ԃសࣁ 12.2±3.3 ྃǴќѦ‫ॺך‬Ψவ஻ ‫ޑޣ‬ӕ΋Ꮲ୔ԏ໣Α 173 Տ଼ந‫ڙ‬၂‫ޣ‬բࣁჹྣಔǴѳ֡ԃសࣁ 12.6±1.5 ྃǶ ҆ᒃᆶঁਢ֡ϩձௗ‫ڙ‬ᆒઓࣽບᘐ‫཮܄‬ፋπ‫ ڀ‬K-SADS-E ‫ޑ‬ຑ՗Ǵаዴҥ ‫ځ‬ບᘐǶ‫ڙ‬၂‫֡ޣ‬ௗ‫ ڙ‬CANTAB ‫ޑ‬ઓ࿶Ј౛ෳᡍǴԜѦǴ‫ॺך‬ΨᒧҔඵΚෳᡍ ύ digit span ٰຑ՗ঁਢ‫ݙុ࡭ޑ‬ཀΚ‫ک‬ᇟ‫ق‬πբ૶ᏫǶऩࢂҞ߻҅ӧܺҔ ADHD ᛰ‫ޑނ‬஻‫ޣ‬Ǵ߾ӧௗ‫ڙ‬ෳᡍϐ߻ԿϿଶЗܺҔᛰ‫ ނ‬24 λਔа΢Ƕԏਢ‫ޑ‬ ௨ନచҹӵΠǺԖᝄख़‫ي‬ᡏ੯ੰӵЈՈᆅ੯ੰǵӄඵ୘λ‫ ܭ‬80ǵᚈཱུ‫܄‬௃ག‫܄‬ ੯ੰੰўǵ‫ނ‬፦ᔲҔੰўǵᆒઓϩ຋ੱੰўǵቶ‫܄ݱ‬ว৖ምᛖੱੰўǵ‫ޣ܈‬ᡜ⻯ ੰў฻Ƕ. 2.1.2.2 ઓ࿶Ј౛ෳᡍǺCABTAB ‫ॺך‬ᒧҔ CANTAB ‫ ޑ‬SSPǵSWMǵIEDǵSOC ຑ՗‫ڙ‬၂‫୺ޑޣ‬ՉфૈǴ٠ а DMSǵPALǵSRMǵPRM ຑ՗‫ڙ‬၂‫ޑޣ‬ຎ᝺૶ᏫфૈǴᜢ‫୺ܭ‬Չфૈෳᡍፎ ‫ ـ‬2.1.1.2ǴаΠ߾ϟಏຎ᝺૶Ꮻ‫ޑ‬ѤঁϩෳᡍǺ. Delayed Matching to Sample (DMS). DMS ࢂຑ՗‫ڙ‬၂‫ޣ‬ჹ‫ܭ‬ፄᚇЪ‫ܜ‬ຝ‫ޑ‬კ ‫׎‬ϐ૶ᏫфૈǴӧ‫؂‬΋ԛෳᡍ໒‫ۈ‬ਔǴ཮Ԗ΋ঁኬҁკ‫׎‬р౜ӧᑻჿύѧऊ 4.5 ࣾǴӧӕਔ௃ნ (simultaneous condition) ύǴ྽ኬҁკ‫׎‬ϝӧᑻჿਔǴѤঁᒧ໨ კ‫׎‬р౜ӧᑻჿΠБǹӧ‫ۯ‬ᒨ௃ნ (delayed condition) ύǴኬҁკ‫׎‬Ӄ੃ѨǴϐ ࡕ࿶ၸ 0 ࣾǵ4 ࣾǵ‫ ܈‬12 ࣾϐࡕǴѤঁᒧ໨კ‫׎‬ω཮р౜ӧᑻჿΠБǴ‫ڙ‬၂‫ޣ‬ ाӧᒧ໨კ‫׎‬ύᒧ‫ڗ‬΋ঁᆶኬҁკ‫ֹ׎‬ӄ΋ठ‫ޑ‬კ‫׎‬ǶനࡕԖѤঁୖኧж߄‫ڙ‬၂ ‫߄ޑޣ‬౜Ǻ(1)ୀෳ‫ډ‬ᒱᇤวғ‫ૈޑ‬Κǹ(2)҅ዴϸᔈ‫ޑ‬ѳ֡ਔ໔ǹ(3)ӧόӕచҹ Π‫҅ޑ‬ዴϸᔈኧҞǹ(4)ӧ҅ዴ‫ک‬ᒱᇤϸᔈϐࡕр౜ᒱᇤ‫ޑ‬ёૈ‫܄‬Ƕ Paired Associates Learning (PAL). PAL ࢂຑ՗‫ڙ‬၂‫ޣ‬ӧຎ᝺კ‫׎‬ᆶຎ᝺‫ޜ‬໔ ‫ޑ‬ᏢಞૈΚǴӧᑻჿ΢཮р౜൳ঁБ༧Ǵ೭٤Б༧཮٩ྣᒿᐒ‫ޑ‬໩‫ׇ‬ԶѺ໒ǴԶ 29.