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1 저작자표시 - 비영리 - 변경금지 2.0 대한민국 이용자는아래의조건을따르는경우에한하여자유롭게 이저작물을복제, 배포, 전송, 전시, 공연및방송할수있습니다. 다음과같은조건을따라야합니다 : 저작자표시. 귀하는원저작자를표시하여야합니다. 비영리. 귀하는이저작물을영리목적으로이용할수없습니다. 변경금지. 귀하는이저작물을개작, 변형또는가공할수없습니다. 귀하는, 이저작물의재이용이나배포의경우, 이저작물에적용된이용허락조건을명확하게나타내어야합니다. 저작권자로부터별도의허가를받으면이러한조건들은적용되지않습니다. 저작권법에따른이용자의권리는위의내용에의하여영향을받지않습니다. 이것은이용허락규약 (Legal Code) 을이해하기쉽게요약한것입니다. Disclaimer

2 의학석사학위논문 3 T-자기공명영상을이용한강박장애환자에서치료반응과관련된뇌회백질의화소기반형태분석연구 Voxel-based morphometric study of gray matter associated with treatment response in obsessivecompulsive disorder patients with 3T-magnetic resonance imaging 2013 년 2 월 서울대학교대학원 의학과정신과학전공 한재욱

3 A thesis of the Master s degree Voxel-based morphometric study of gray matter associated with treatment response in obsessive-compulsive disorder patients with 3T-magnetic resonance imaging 3 T- 자기공명영상을이용한강박장애 환자에서치료반응과관련된뇌회백질의 화소기반형태분석연구 February 2013 The Department of Psychiatry Seoul National University College of Medicine Jae Wook Han

4 초록 서론 : 이전부터강박장애의병태생리와관련한신경해부학적이상을규명하기위해많은뇌영상연구들이진행되어왔다. 그러나강박장애의치료반응과관련된뇌영역에대해서는소수의연구들이진행되었으며, 기존연구들은대상표본의크기가작고일관된결과들이보고되고있지않아추가적인연구가필요한상태이다. 이에본연구에서는화소기반형태분석방법을이용하여강박장애환자중치료비반응군과치료반응군을대상으로치료반응과관계가있는뇌영역을알아보고자하였다. 방법 : 치료전과치료 4개월후예일-브라운강박척도총점의호전정도에따라분류된 29명의치료비반응군과 19명의치료반응군이연구에참여하였다. 치료전 3 테슬라자기공명영상검사를시행하여획득한영상을화소기반형태분석방법을이용해처리하였다. 각군사이에회백질용적차이의유의성을검정하기위해부피소단위공분산분석을시행하였다. 차이를보인뇌영역의회백질용적과예일-브라운강박척도점수의변화사이의상관관계를알아보기위해비모수상관분석을시행하였다. i

5 결과 : 강박장애환자군중치료비반응군은치료반응군과비교하였을때치료전오른쪽안와전두엽과왼쪽뒤쪽띠이랑의회백질용적이유의하게감소된소견을보였다. (uncorrected p<0.001) 오른쪽하측두이랑의경우치료비반응군에서치료반응군에비하여회백질용적이증가된소견을보였다. (uncorrected p<0.001) 치료비반응군에서치료전안와전두엽의회백질용적과 4개월동안예일-브라운강박척도점수의호전정도는유의한양적상관관계를보였다. 결론 : 본연구에서치료비반응군은치료반응군에비해기저안와전두엽과뒤쪽띠이랑의회백질용적이감소된소견을보였고특히치료비반응군내에서안와전두엽의회백질용적은치료전후예일-브라운강박척도점수의호전정도와유의한양적상관관계를보였다. 이결과는강박장애환자들에서이들부위의구조적이상이추후치료반응을예측할수있는신경해부학적표지자로이용될수있을가능성을시사한다 주요어 : 강박장애, 치료반응, 치료저항성강박장애, 화소기반형태분석방법, 안와전두엽, 뒤쪽띠이랑학번 : ii

6 목차 초록 i 목차 iii List of Tables iv List of Figures v List of Abbreviations vi I. 서론 II. 연구대상및방법 III. 연구결과 IV. 고찰 V. 참고문헌 Abstract iii

7 List of Tables Table 1. Summary of previous structural neuroimaging studies regarding refractoriness and prediction of treatment response in obsessive-compulsive disorder patients Table 2. Summary of previous functional neuroimaging studies regarding refractoriness and prediction of treatment response in obsessive-compulsive disorder patients Table 3. Demographic and clinical characteristics of treatment responding and treatment non-responding obsessive-compulsive disorder patients iv

8 List of Figures Figure 1. Summary of voxel-based morphometry procedure administrated in T1-weighted gray matter images of obsessive-compulsive disorder patients acquired with 3T-MRI instrument Figure 2. Comparison of Y-BOCS total score change between treatment responding and treatment non-responding obsessive-compulsive disorder patients Figure 3. Areas of which gray matter were smaller in treatment nonresponding patients than in treatment responding obsessive-compulsive disorder patients Figure 4. Areas of which gray matter were larger in treatment non-responding patients than in treatment responding obsessive-compulsive disorder patients Figure 5. Scatter plot which shows the correlation between gray matter density of right orbitofrontal cortex and change of Y-BOCS total score of treatment non-responding obsessive-compulsive-disorder patients v

9 Abbreviations ACC: anterior cingulate cortex BAI: Beck Anxiety Inventory BDI: Beck Depression Inventory CBT: cognitive-behavioral therapy CGI-I: Clinical Global Impression-Improvement rating scale CSF: cerebrospinal fluid DLPFC: dorsolateral prefrontal cortex DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition fmri: functional Magnetic Resonance Imaging GM: gray matter GMD: gray matter density GMV: gray matter volume K-WAIS: Korean version of the Wechsler Adult Intelligence Scale MDD: major depressive disorder mpfc: medial prefrontal cortex MRS: Magnetic Resonance Spectroscopy OCD: obsessive-compulsive disorder OFC: orbitofrontal cortex PCC: posterior cingulate cortex PET: Positron Emission Tomography rcbf: regional cerebral blood flow RCFT: Rey-Osterrieth Complex Figure Test ROI: Region of Interest vi

10 SCID: Structured Clinical Interview for DSM-IV SPECT: Single Photon Emission Computed Tomography SSRI: selective serotonin reuptake inhibitor STG: superior temporal gyrus VBM: Voxel-Based Morphometry WM: white matter Y-BOCS: Yale-Brown Obsessive Compulsive Scale vii

11 I. 서론 1. 강박장애의개요 강박장애 (obsessive-compulsive disorder, OCD) 는평생유병률이전체인구의 2~3% 에이르는상당히흔한정신과질환이며 (1-4) 정신질환중에서는공포증, 우울증, 물질사용장애에이어네번째로흔하다.(5) 정신장애의진단및통계편람제 4판 (Diagnostic and Statistical Manual of mental disorder, fourth edition, DSM-IV)(6) 에따르면강박장애는부정적인외부자극과관련된반복적이고침투적인강박사고 (obsession) 와이를중화시켜불안을감소시키고자하는엄격하고융통성없는 (rigid) 강박행동 (compulsion) 을특징으로하는불안장애의하나이다. 강박장애에서나타나는강박사고와강박행동은과도하고 (excessive) 비합리적인 (unreasonable) 것을주요한특징으로하는데대부분의환자들이이를인식하지만통제하지못해고통을받으며직업적, 학업적, 사회적기능의저하를겪는다.(7) 오늘날강박장애의표준적인치료는크게약물치료와인지행동치료로구분된다. 약물치료에가장일반적으로사용되는약물은선택적세로토닌재흡수억제제 (selective serotonin reuptake inhibitor, SSRI) 이다. 그러나실제강박장애환자의경우 40% 에서많게는 60% 의환자들이세로토닌재흡수억제제에잘반응하지않으며재발과악화를반복하는만성적인경과를밟는다.(8-14) 1

12 2. 강박장애의뇌영상연구 강박장애에서자기공명영상을통한뇌영상연구는 1980년대후반부터시작되었고주로강박장애의병태생리와밀접한관계가있는피질-줄무늬체-시상-피질회로 (cortico-striato-thalamo-cortical circuit) 를구성하는뇌의부위, 특히안와전두엽 (orbitofrontal cortex, OFC) 과바닥핵을위주로이루어졌다. 바닥핵은대뇌피질로부터들어오는정보들을걸러내는역할을하는데이부위의장애는강박장애의증상형성에중요한역할을한다.(15-17) 강박장애의구조적뇌영상연구들은기능적뇌영상연구들에비해상대적으로일관된보고가적은편이며꼬리핵, 조가비핵등기저핵과안와전두엽을비롯한전전두엽의용적변화가주로보고되었다.(18-24) 강박장애의구조적뇌영상연구들에비해기능적뇌영상연구들은비교적일관된결과들을보고하였으며기저핵과시상, 안와전두엽, 앞쪽띠이랑등의이상이주로보고되었다.(25-32) 한편기존의뇌영상연구들에서주로사용된방법은관심영역지정방법 (region of interest, ROI) 인데, 측정하고자하는뇌영역을명확하게정의하고주변의뇌영역이포함되지않도록하기가어려워방법론적인제한점이있었다. 이제한점을극복하기위해시도된방법이화소기반형태분석방법 (Voxel-Based Morphometry, VBM) 으로인위적인구획설정없이전체적인뇌영역에서의변화를찾을수있는방법이다. 강박장애에서는김재진등이처음으로적용을했는데피질-줄무늬체회로를구성하는뇌영역에서회백질 2

13 밀도의증가를보고하였고이외에도강박장애의병태생리와두정엽, 소뇌의연관성을제시하였다.(33) VBM을이용한이후의연구들역시안와전두엽의이상을보고하였으며바닥핵, 소뇌와의연관성 (34, 35), 측두변연계와두정엽의이상 (36-39) 그리고앞쪽및뒤쪽띠이랑 (posterior cingulate cortex, PCC) 의이상 (40) 등을보고하였다. 3. 강박장애의치료저항성및치료반응예측과관련 뇌영상연구 강박장애의치료반응에있어서 치료비반응자 (non-responder), ' 치료저항성 (treatment-resistant)' 그리고 난치성 (treatmentrefractory) 과같은표현들이각각다른의미로사용되기도했고때로는동의어처럼사용되기도하였다. 이처럼치료반응에대한개념이혼란스러운상황에서 2006 년 Pallanti 등은여러의견들을반영하여치료반응을일곱단계로구분하고각각의단계를정의하였는데, 이중 비반응 (non-reponse) 은 5 단계로치료전후예일-브라운강박척도총점의감소가 25% 이하인경우또는임상총괄평가-호전도 (Clinical Global Impression-Improvement rating scale, CGI-I) 가 4 인경우가이에해당한다.(41) 치료저항성강박장애에대한구조적뇌영상연구 ( 표 1) 로는 2006 년 Atmaca 등이발표한연구가있다.(42) 이연구에서 저자들은각 10 명의치료경험이없는군, 치료반응군그리고 치료저항성환자군으로구성된총 30 3 명의강박장애환자들을

14 대상으로 ROI 분석을시행하였는데안와전두엽의용적감소와시상의용적증가가강박장애의치료저항성과관련이있다고보고하였다. 또한저자들은 ROI 를이용한추후연구에서각 14 명의치료저항성강박장애환자군과정상대조군을비교하였을때치료저항성강박장애환자군에서양측해마와편도체용적이정상대조군에비해감소되어있음을보고하였다.(43) 강박장애의치료반응예측과관련된기능적뇌영상연구들 ( 표 2) 에서는양전자방출단층촬영 (Positron Emission Tomography, PET) 에서안와전두피질의대사나뇌혈류가낮을수록약물치료반응이좋다는결과가가장일관되게보고되었다.(44-46). 한편자기공명분광촬영 (Magnetic Resonance Spectroscopy, MRS) 연구에서치료전안와전두엽의마이오이노시톨농도가인지행동치료에대한반응정도와연관이있다고보고되었고,(47) Hoexter 등은안와전두엽과내측전전두엽의회백질용적이각각약물치료와인지행동치료에대한반응정도와상관관계가있다고보고하였다.(48) 그외뒤쪽띠이랑의혈류나 (46) 꼬리핵의대사가높을수록 (49) 치료반응이우수하다는결과도있다. Sanematsu 등은치료전소뇌와상측두이랑 (superior temporal gyrus, STG) 의활성과강박증상의호전사이에양적상관이있음을보여주었다.(50) 요약하면강박장애환자에서치료저항성과연관된뇌영역으로는안와전두엽, 시상, 해마, 편도체등이추정되고있으며치료반응예측과연관된뇌영역으로는안와전두엽, 내측전전두엽, 띠이랑, 꼬리핵, 소뇌, 상측두이랑등이추정되고있다. 특히강박장애 4

15 환자에서안와전두엽의이상과치료반응과의연관성은여러 연구들에서비교적일관되게보고되어왔다. 5

16 Table 1. Summary of previous structural neuroimaging studies regarding refractoriness and prediction of treatment response in obsessivecompulsive disorder patients Authors Modality Subject number Comparison & Study design Findings Atmaca et al.(42) MRI (ROI) 40 (10/10/10/10) First applying / Treatment-responded / Refractory / Control Smaller OFC and greater thalamic volume in refractory OCD patients than in treatment-responded patients. Atmaca et al.(43) MRI (ROI) 28 (14/14) OCD / Control Smaller hippocampal and amygdalar volume in refractory OCD patients. OCD severity was related to the hippocampus. Duration of illness was correlated with both hippocampus and amygdala. Hoexter et al.(48) MRI (VBM) 29 (14/15) Fluoxetine/ CBT Symptom improvement in fluoxetine group was correlated with smaller pre-treatment GMV within OFC, whereas symptom improvement in CBT group was correlated with larger pre-treatment GMV within mpfc. Abbreviations: GMV, gray matter volume; mpfc, medial prefrontal cortex; OCD, obsessive-compulsive disorder; OFC, orbitofrontal cortex; ROI, region of interest 6

17 Table 2. Summary of previous functional neuroimaging studies regarding refractoriness and prediction of treatment response in obsessivecompulsive disorder patients Authors Modality Subject number Comparison & Study design Findings Zurowski et al.(47) MRS 25 (16/9) OCD / Control Concentration of myoinositol in OFC predicted the outcome of subsequent CBT regarding Y- BOCS score reduction. Brody et al.(44) PET 27 No control Saxena et al.(45) PET 20 No control Higher pre-treatment metabolic activity in OFC was associated with a better response to behavioral therapy. In contrast, lower OFC metabolic activity was associated with a better response to treatment with fluoxetine. In patients who responded to paroxetine, glucose metabolism decreased in OFC and caudate nucleus. Lower pre-treatment metabolism in bilateral OFC predicted greater improvement in OCD severity with treatment. 7

18 Rauch et al.(46) PET 9 No control Lower rcbf values in OFC and higher rcbf values in PCC predicted better treatment response with fluvoxamine. Saxena et al.(49) PET 71 (27/27/17) OCD alone / MDD alone / Concurrent OCD and MDD Improvement of OCD symptoms was correlated with higher pre-treatment glucose metabolism in the caudate nucleus. Sanematsu et al.(50) fmri 15 No control Pre-treatment activation in STG and cerebellum was positively correlated with the improvement in the Y-BOCS score. Abbreviations: CBT, cognitive-behavioral therapy; fmri, functional magnetic resonance imaging; MDD, major depressive disorder; MRS, magnetic resonance spectroscopy; OCD, obsessive-compulsive disorder; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PET, positron emission tomography; rcbf, regional cerebral blood flow; STG, superior temporal gyrus; Y-BOCS, Yale-Brown Obsessive Compulsive Scale 8

19 4. 본연구의목적 이상에서살펴본바와같이강박장애의치료저항성및치료반응 예측과연관된뇌영역에대한연구들이시행되었지만연구의수가 적고연구에동원된표본의크기가작으며, 특히구조적뇌영상 연구의경우 ROI 방법을이용한연구가많았다. 따라서본 연구에서는 VBM 을적용하여보다큰표본을대상으로강박장애의치료반응과관련된뇌영역을알아보고자하였다. 본연구의목적을구체적으로기술하면다음과같다. 첫째, 강박장애환자중치료비반응군과치료반응군의기저뇌영상을비교하여강박장애의치료반응을예측할수있는신경해부학적표지자를규명한다. 둘째, 강박장애환자에서상기뇌영역의이상과치료전후강박증상의변화정도간상관관계를알아본다. 9

20 II. 연구대상및방법 1. 연구대상자 제일축정신과진단이강박장애인 48명의환자를연구대상으로하였다. 모든환자는서울대학교병원강박증클리닉을내원한환자를대상으로모집하였으며, 정신과적진단은 DSM-IV을위한구조화임상면접 (Structured Clinical Interview for DSM-IV, SCID)(51) 을이용하여 DSM-IV의강박장애진단기준에따라진단하였다. 정신과약물사용력이없거나, 적어도최근 4주이내에는정신과약물을복용하지않은경우에만연구참여가허용되었다. 본연구에참여한환자군의연령은 15~48세사이였으며, 지능지수 70 미만, 다른내과적장애, 신경학적장애를가지고있는경우, 약물이나알코올중독의병력이있는경우, 현재뇌기능에영향을미칠한약물을복용하는경우, 두부손상의병력이있는경우는연구에서배제하였다. 환자군중 16명은약물사용력이없었으며 (drug-naive), 32명의환자는연구시작시점기준으로 4주이상약물을복용하지않고있는 (unmedicated) 상태였다. 치료시작 4개월후의예일-브라운강박척도 (Yale-Brown Obsessive Compulsive Scale, Y-BOCS)(52, 53) 점수가기저 (baseline) 측정치와비교하여악화되었거나호전정도가 30% 미만인경우를치료비반응군 (treatment non-responder) 으로, 호전정도가 30% 이상인경우를치료반응군 (treatment responder) 으로정의하였다. 이러한기준에따라 48명의환자군은각각 29명의치료비반응군과 19명의치료반응군으로 10

21 분류되었다. 연구대상자들은연구참여에앞서연구의목적과과정에대하여충분히설명을들었고모두자발적의사를통해연구참여에동의하였으며, 서면으로동의서 (written informed consent) 에자필서명하였다. 본연구는서울대학교병원의학윤리심의위원회의승인을받고수행되었다. 2. 임상적평가 기저와치료시작후 4 개월에 Y-BOCS 를시행하여강박증상의심각도를평가하였고, 우울증상과불안증상의심각도를평가하기위해서는벡우울척도 (Beck Depression Inventory, BDI)(54) 와벡불안척도 (Beck Anxiety Inventory, BAI)(55) 를각각시행하였다. 지능 (IQ) 은한국판웩슬러성인지능검사 (the Korean version of the Wechsler Adult Intelligence Scale, K-WAIS)(56) 중어휘, 산수, 토막짜기, 차례맞추기소항목을검사하여추정치를측정하였다. 손잡이는아네트손잡이설문지 (Annett s hand preference questionnaire)(57) 로평가하였다. 3. 자기공명영상획득 뇌영상은 3 테슬라장비 (MAGNETOM Trio Tim Syngo MR B17 Scanner; Siemens, Erlangen, Germany) 를이용하여획득하였다. 3차원 T1-강조 자화준비고속경사에코 (magnetization-prepared rapid- 11

22 acquisition gradient echo, MPRAGE) 영상의촬영변수는아래와같다 : 반복시간 (repetition time, TR) = 1.67 s, 에코시간 (echo time, TE) = 1.89 ms, 영상범위 (field of view, FOV) = 250 mm, 숙임각 (flip angle, FA) = 9, 부피소 (voxel) 크기 = 0.9x0.9x1 mm. 총 208장의 image volume이촬영되었다. 4. 화소기반형태분석을위한영상자료처리 자기공명영상을이용한최적화화소기반형태분석은 Good 등 (58) 이제안한방법을이용하였으며, 영상자료의분석은 FMRIB Software Library(FSL) 의일부인 FSL-VBM( 을이용하여시행되었다. 먼저 FSL의 Brain Extraction Tool(BET) 을이용하여연구대상자 48명의뇌자기공명영상으로부터뇌구조물만을추출하였다. 이후 FMRIB's Automatic Segmentation Tool(FAST) 을이용하여추출된영상으로부터회백질과백질을분리하였다. 추출된회백질의부분부피영상들을 non-linear registration tool인 FMRIB's Nonlinear Image Registration Tool(FNIRT) 을이용하여 Montreal Neurological Institute 표준공간 (MNI 152) 으로등록 (registration) 하였다. 등록된부분부피영상들은등록과정중발생할수있는영상의국소확장이나축소를보정하기위해 warp field의 Jacobian determinant 들을이용하여회백질의화소를변조 (modulation) 시켰다. 이렇게분할되고변조된영상들을 2 mm 가우시안커널 (σ=2mm) 을이용하여편평화 (smoothing) 하였다. 본연구의전반적인영상자료처리과정을그림1에요약하였다. 12

23 5. 통계적분석 위와같이처리된영상자료를바탕으로치료비반응군과치료반응군간의비교를위해각집단의연령과성별을통제하여 voxelwise analysis of covariance(ancova) 를시행하였다. Cluster들의통계적의의를분석하기위해 threshold-free cluster enhancement(tfce) 방법을이용하였고 permutation-based non-parametric testing(5,000 permutation) 을시행하였다. 이과정에서통계적유의수준은 p<0.001(uncorrected) 또는 family wise error(fwe) p <0.05로설정하였고범위역치는 50 부피소로설정하였다. 화소기반형태분석에서치료반응군과치료비반응군사이에유의한차이를보인뇌영역에대해서는회백질용적을별도로계산하였고, 이렇게얻어진각영역들의회백질용적과 4개월동안 Y- BOCS 점수의변화정도의상관관계를알아보기위해비모수상관분석을시행하였다. 치료반응군과치료비반응군사이성별을제외한인구학적변수와 IQ, BAI, BDI, 기저및 4 개월후의 Y-BOCS 점수를이-표본 t-검정을이용하여비교하였고성별과과거약물치료여부는카이제곱검정을이용하여비교하였다. Y-BOCS 점수는강박사고 (O: Obsession) 항목점수, 강박행동 (C: Compulsion) 항목점수그리고 총점을나누어비교하였으므로 Bonferroni correction 을적용하여 통계적유의수준을 p<0.017(0.005/3) 로설정하였으며이를제외한 나머지변수들은통계적유의수준을 p<0.05 로설정하였다. 통계 13

24 분석은 IBM SPSS Statistics 19 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA) 를사용하였다. 14

25 Figure 1. Summary of voxel-based morphometry procedure administrated in T1-weighted gray matter images of obsessive-compulsive disorder patients acquired with 3T-MRI instrument Structural data was analyzed with FSL-VBM(FMRI Software Library, an optimized VBM protocol carried out with FSL tools. (A) Image acquisition was performed with 3T-MRI instrument (MAGNETOM Trio Tim Syngo MR B17 Scanner; Siemens, Erlangen, Germany) in 19 treatment responding and 29 treatment non-responding OCD patients. (B) From the acquired T1-weighted MR images, (C) only brain images were extracted using brain extraction tool(bet). (D) All brain extracted images were segmented into GM, WM and CSF, (E) then GM images were registered to MNI standard template using non-linear registration. Each voxel of each registered GM image was multiplied by the Jacobian of the warp field to modulate the contraction or enlargement due to the non- 15

26 linear component of the transformation. All the modulated GM images were smoothed with 2 mm Gaussian kernel. (F) Permutation-based non-parametric testing was performed and TFCE-based thresholding results were displayed. (uncorrected p<0.00 or FEW p <0.05) Abbreviations: CSF, cerebrospinal fluid; GM, gray matter; MNI, Montreal Neurological Institute; MRI, Magnetic Resonance Imaging; OCD, obsessivecompulsive disorder; TFCE, threshold-free cluster enhancement; VBM, voxel-based morphometry; WM, white matter 16

27 III. 연구결과 1. 연구대상자의특징 본연구에참여한대상자의인구학적및임상적특징을표2에기술하였다. 치료반응군과치료비반응군사이에연령을제외한다른인구학적변수들의유의한차이는없었다. BAI, BDI로평가한우울, 불안정도또한두군사이에통계적으로유의한차이는없었다. 기저 Y-BOCS 강박사고항목점수는이-표본 t-검정을시행했을때 p값이 0.035였지만 Bonferroni correction으로사후분석을한결과유의한차이가없었다.(p>0.017=0.005/3) 치료 4개월후치료반응군은치료비반응군에비해서 Y-BOCS 강박사고항목점수, 강박행동항목점수및총점모두유의하게낮았다. 그림2는치료반응군과치료비반응군의기저및치료 4개월후예일-브라운강박척도총점의변화를비교한것이다. 17

28 Table 3. Demographic and clinical characteristics of treatment responding and treatment non-responding obsessive-compulsive disorder patients Treatment responding patients (N=19) Treatment non-responding patients (N=29) t a or χ 2b p Age, years 23.84± ± a * Sex (F/M) 8/11 11/ b Handedness (R/L) 19/0 29/0 - - Education, years 13.84± ± a IQ ± ± a Medication (naive/free>4wk) 4/15 12/ b BAI score 14.17± ± a BDI score 16.06± ± a Y-BOCS score (baseline) Obsession 13.79± ± a c Compulsion 12.42± ± a Total 26.21± ± a Y-BOCS score (4 months later) Obsession 6.05± ±3.16 (N=28) a <0.001 * Compulsion 6.21± ±4.34 (N=28) a <0.001 * Total 12.26± ± a <0.001 * 18

29 Data are presented as mean± SD unless otherwise indicated. a Two-sample t-test b Chi-square test c not significant after Bonferroni correction (p> 0.017) * p-value < Abbreviations: F/M, Female/Male; IQ; intelligent quotient; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; Y-BOCS, Yale Brown Obsessive Compulsive Scale 19

30 Y-BOCS total score Figure 2. Comparison of Y-BOCS total score change between treatment responding and treatment non-responding obsessive-compulsive disorder patients Error bars mean ± 1SD. * p-value < Abbreviations: Y-BOCS, Yale-Brown Obsessive Compulsive Scale 20

31 2. 뇌영상자료 치료비반응군에서치료반응군과비교하였을때회백질용적이유의하게감소된부위는오른쪽안와전두엽과왼쪽뒤쪽띠이랑이었다.( 그림 3, t=3.762, p<0.001, cluster>50, uncorrected for multiple comparison) 반면오른쪽하측두이랑의회백질용적은치료비반응군에서치료반응군에비하여증가된소견을보였다.( 그림 4, t=3.113, p<0.001, cluster>50, uncorrected for multiple comparison) 21

32 Figure 3. Areas of which gray matter were smaller in treatment nonresponding patients than in treatment responding obsessive-compulsive disorder patients (A) Right OFC: k=60; t= ; uncorrected p (peak)= ; x y z coordinate [ ] (B) Left PCC: k=90; t= ; uncorrected p (peak)= ; x y z coordinate [4-48 2] Cortical t-statistical maps were rendered by BrainNet Viewer ( Abbreviations: OFC, orbitofrontal cortex; PCC, posterior cingulate cortex 22

33 Figure 4. Areas of which gray matter were larger in treatment non-responding patients than in treatment responding obsessive-compulsive disorder patients Right ITG: k=51; t= ; uncorrected p (peak)= ; x y z coordinate [ ] Cortical t-statistical maps were rendered by BrainNet Viewer ( Abbreviations: ITG, inferior temporal gyrus 23

34 3. 회백질용적과 Y-BOCS 점수변화정도의상관관계 분석결과유의한차이를보인오른쪽안와전두엽, 왼쪽뒤쪽띠이랑그리고오른쪽하측두이랑에대해서는회백질용적을별도로계산하였고, 이렇게얻어진각영역들의회백질용적과 4 개월동안의 Y-BOCS 점수변화정도간상관관계를알아보기위해상관분석을시행하였다. 비모수상관분석을시행한결과치료비반응군에서오른쪽안와전두엽의회백질용적은 4 개월동안 Y- BOCS 총점의변화와유의한수준의양적상관관계를보였다.(Kendall s tau-b correlation coefficient=0.310, p=0.019, 그림 5) 즉, 치료비반응군에서오른쪽안와전두엽의회백질용적이작을수록 4 개월동안 Y-BOCS 총점의호전정도가작았다. 그리고치료비반응군에서왼쪽뒤쪽띠이랑의회백질용적과 4 개월동안 Y- BOCS 총점의변화사이에경향성수준의 (trend level) 양적상관관계를보였다.(Kendall s tau-b correlation coefficient=0.235, p=0.074) 한편전체강박장애환자군과치료반응군내에서는상기 뇌영역들의회백질용적과 Y-BOCS 총점의변화사이에유의한 상관관계가관찰되지않았다. 24

35 Change of Y-BOCS score % Figure 5. Scatter plot which shows the correlation between gray matter density of right orbitofrontal cortex and change of Y-BOCS total score of treatment non-responding obsessive-compulsive-disorder patients Abbreviations: GMD, gray matter density; OCD, obsessive-compulsive disorder; OFC, orbitofrontal cortex; Y-BOCS, Yale-Brown Obsessive Compulsive Scale 25

36 IV. 고찰 1. 연구결과요약 본연구는저자가조사한바로는강박장애환자중치료비반응군과치료반응군을대상으로화소기반형태분석방법을적용하여치료반응과관련된뇌영역을조사한최초의뇌영상연구이다. 강박장애환자군을 4개월간의치료반응에따라치료반응군과치료비반응군으로구분하였을때, 치료비반응군은치료반응군에비해오른쪽안와전두엽과왼쪽뒤쪽띠이랑의회백질용적은감소되어있고오른쪽하측두이랑의회백질용적은증가된소견을보였다. 그리고치료비반응군내에서기저오른쪽안와전두엽의회백질용적은 4개월동안 Y-BOCS 총점의호전정도와양적상관관계를보였다. 본연구에서는정신과약물사용력이없거나, 적어도최근 4주이내에는정신과약물을복용하지않은경우에만연구참여가허용되었기때문에약물이연구결과에미치는영향을최소화하였다. 그리고연구참여자들을 4개월동안추적관찰하여기저와 4개월후에 Y-BOCS 를시행하여치료반응을객관적으로평가하였다. 2. 안와전두엽과강박장애의치료반응 앞서언급했듯이안와전두엽은강박장애의병태생리와밀접한관계가있는피질-줄무늬체회로의일부로강박장애연구의주된관심영역이었다. 강박장애환자들과정상대조군을비교한기존의 26

37 뇌영상연구들은강박장애환자군에서안와전두엽의용적감소를보고하였다.(22, 24) 한편, 안와전두엽의앞쪽부분은인지기능과관련된작업을수행하는데더많이관여하고등외측전전두피질 (dorsolateral prefrontal cortex, DLPFC), 앞쪽띠이랑과상호연결성을보이며, 뒤쪽부분은감정처리능력과더밀접한관련을보이며편도등과연결되어있다.(59) 이에최정석등은해부학적외부표지자를이용하여안와전두엽을전후로나눠각각의용적을비교하였는데강박장애환자군에서앞쪽안와전두엽의용적이감소되어있었고, 이것은레이복합도형검사 (Rey-Osterrieth Complex Figure Test, RCFT) 의모사점수 (copy score) 와유의한양적상관관계를보였다.(23) 즉, 앞쪽안와전두엽의용적감소가강박장애환자들에서보이는조직화능력의장애와밀접한관계를보인다는것이다. 또한 Chamberlain 등은 fmri를이용한연구에서행동적융통성을요구하는과제를수행할때강박장애환자뿐아니라그친족들에서도정상대조군에비해안와전두엽의활성이유의하게감소되어있음을보고하였다.(61) 이를종합해보면안와전두엽의구조적, 기능적이상은강박장애환자들에서나타나는특정인지기능의저하와연관이있으며, 강박장애에대한취약성지표 (vulnerability marker) 일가능성이있다. 한편본연구에서는치료비반응군에서치료반응군에비해치료전안와전두엽의회백질용적이유의하게감소되어있음이관찰되었다. 그리고서론에서언급하였듯이 Atmaca 등은치료저항성강박장애환자에서치료반응군에비해안와전두피질이유의하게감소되어있음을보고한바있다.(42) 요컨대강박장애환자내에서도안와전두엽의용적감소정도에차이가있으며이러한 27

38 차이는치료저항성또는치료반응과연관이있을가능성이있다. 이러한연관성은본연구에서치료비반응군의치료전안와전두엽회백질용적과 4개월동안 Y-BOCS 총점의호전정도사이에양적상관관계가관찰된것으로더욱뒷받침된다. 뿐만아니라앞서살펴보았듯이강박장애의치료반응예측과관련된기존의뇌영상연구들도치료전안와전두엽의활성및용적이추후치료반응과연관이있음을비교적일관적으로보고하고있다.(44-46, 48) 본연구와기존연구들의결과를종합해보면강박장애환자에서치료전안와전두엽의구조적, 기능적이상은추후치료반응을예측할수있는신경해부학적표지자로이용될가능성이있으며, 추후이에대한확인이필요할것으로생각된다. 3. 뒤쪽띠이랑과강박장애의치료반응 안와전두엽과마찬가지로띠이랑역시강박장애의병태생리와밀접한관계가있는부위로많은연구들이이루어졌다. 띠이랑은해부학적위치에따라앞쪽띠이랑과뒤쪽띠이랑으로구분된다. 앞쪽띠이랑은신피질중에서감정과인지행동을조절하고 (62) 집행하는과정에서주요한역할을담당하는부위이다.(63, 64) 몇몇연구들에서강박장애환자들이집행기능과시각적기억력의이상등몇몇인지기능의장애를보이며, 이러한이상이앞쪽띠이랑의기능이상과관련될가능성에대해언급하였다.(65-67) 뇌영상연구에서는강박장애환자들에서앞쪽띠이랑의회백질용적감소 (36, 40) 백질용적감소 (68), N-아세틸아스파테이트감소 (69), 글루타 28

39 메이트-글루타민농도감소 (70) 그리고휴지기와증상유발시과활성 (71) 등의구조적, 기능적이상소견들이흔히보고되어왔다. 한편뒤쪽띠이랑, 특히등쪽뒤쪽띠이랑 (dorsal posterior cingulate cortex, dpcc) 은인지과정중에서도비감정적인지과정 (nonemotional cognitive process) 과관련이있다고알려져있다.(72) Matsumoto 등은 VBM 방법을사용한연구에서강박장애환자에서정상대조군에비해앞쪽띠이랑과뒤쪽띠이랑의일부회백질용적이유의하게감소되어있음을보고하였고이러한구조적이상이강박장애환자에서인지적갈등을조절하는능력이손상되어있는것과관련이있을가능성을제시하였다.(37, 40) 치료비반응군에서치료전뒤쪽띠이랑의회백질용적감소가관찰된본연구의결과는이상에서언급한뒤쪽띠이랑과관련된인지기능의이상이치료비반응군에서치료반응군에비해더심하고, 이러한기능저하가치료전부터존재할가능성을시사한다. 저자가조사한바로현재까지치료비반응군과치료반응군의치료전인지기능차이를비교한연구는없으므로추후이에대한연구가필요할것으로생각된다. 띠이랑과강박장애의치료반응에대해서는비교적소수의연구들이있는데 Rauch 등은 PET를이용한연구에서뒤쪽띠이랑의혈류가높을수록약물치료에대한반응이우수하다는결과를보고하였다.(46) 본연구에서는치료비반응군에서치료반응군에비해치료전왼쪽뒤쪽띠이랑의회백질용적이감소되어있었는데, 저자가조사한바로이는강박장애의치료반응과관련된구조적뇌영상연구에서는처음으로보고되는것이다. 한편앞쪽띠이랑과강박장애의치료반응과관련하여 Hendler 등은 SPECT를사용한연구 29

40 에서치료반응군이치료비반응군에비하여증상유발시앞쪽띠다발의등쪽-꼬리쪽부위 (dorsal-caudal anterior cingulum) 의혈류가감소되어있음을보고하였다.(73) 위의결과들을종합해보면앞쪽및뒤쪽띠이랑의구조적, 기능적이상이강박장애의병태생리뿐만아니라치료반응과도연관될가능성이있으며이에대한추가적인연구가필요할것으로사료된다. 4. 하측두이랑과강박장애의치료반응 기존뇌영상연구들에서강박장애의병태생리에피질- 줄무늬체회로의이상이외에도측두-변연계 (temporo-limbic system) 의이상이관여할가능성이시사되었으며특히상측두이랑과해마의용적감소그리고편도용적의증가등이보고되었다.(60, 74) 본연구에서는치료비반응군에서치료반응군과비교했을때치료전오른쪽하측두이랑의회백질용적이증가된소견이관찰되었는데, 하측두이랑과강박장애와관련성에대한기존의연구는희박하다. Phillips 등은강박장애환자들을우세한증상에따라세척유형 (washer) 과확인유형 (checker) 으로구분하여비교한 fmri 연구에서증상관련자극을주었을때유형에따라하측두이랑을비롯한다양한뇌영역들의활성에차이가있음을보고한바있다.(75) 또한하측두이랑의회백질용적감소가우울장애 (76) 및조현병과 (77) 관련이있다는보고가있는데강박장애환자들에서동반될수있는우울증상또는정신증적수준의기이한강박증상 (bizarre obsessive-compulsive symptoms) 이 30

41 하측두이랑의구조적이상에영향을미칠가능성을고려해야할 것으로생각된다. 한편강박장애의치료반응과관련해서 Sanematsu 등은강박장애 환자들을대상으로한 fmri 연구에서 플루복사민약물치료전후 Y-BOCS 총점을비교하였을때, 치료전상측두이랑의활성과증상의호전사이에양적상관관계가있음을보고한바있다.(50) 비록본연구에서상측두이랑과치료반응의상관관계는관찰되지않았지만추후상측두이랑을포함하여측두엽부위와강박장애의치료반응사이의관계에대해추가적인연구가필요할것으로생각된다. 5. 본연구의제한점 본연구에참여한강박장애환자들이 BDI 점수상으로경도 (mild) 내지는중등도 (moderate) 의우울수준을보고한것을감안할때, 연구대상자들의우울증상이결과에영향을미쳤을가능성이있다. 단, 본연구의대상자들중에서 DSM-IV의우울장애진단기준을만족하는경우는없었다. 그리고본연구에서는세척유형이나확인유형등우세한강박증상에따른분류를하지않았기때문에강박증상의유형에따른차이는알수없었다. 추후연구에서는이를보완하여추가적인분석을해보는것이필요하겠다. 6. 결론 31

42 본연구에서는강박장애환자들중치료비반응군에서치료반응군에비해치료전오른쪽안와전두엽과왼쪽뒤쪽띠이랑의유의한회백질용적감소가관찰되었다. 그리고치료비반응군내에서오른쪽안와전두엽의회백질용적과 4 개월동안 Y-BOCS 총점의호전정도는유의한양적상관관계를보였다. 본연구의결과는안와전두엽및띠이랑의구조적, 기능적이상이강박장애의병태생리와관련이있다는기존의연구들을지지하는한편, 강박장애환자에서치료전이들부위의구조적이상이추후치료반응을예측할수있는신경해부학적표지자로이용될수있을가능성을시사한다. 32

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49 Abstract Introduction: Numerous brain imaging studies have been conducted to identify the neuroanatomical abnormalities related with the pathophysiology of obsessive-compulsive disorder (OCD). However, regarding the brain regions associated with the treatment response of OCD, there are only a few studies of small sample size, which have reported inconsistent findings. In this study, using voxel-based morphometry (VBM), treatment-responding patients and treatment non-responding patients were evaluated to identify the brain regions associated with the treatment response of OCD. Methods: Nineteen treatment responding patients and twenty-nine treatment non-responding patients classified by the degree of improvement in Yale- Brown Obsessive Compulsive Scale (Y-BOCS) score between the baseline and 4 months later participated in this study. Images obtained before treatment by 3-Tesla magnetic resonance imaging were processed using VBM. Voxelwise analysis of covariance (ANCOVA) has been performed to identify the significance of gray matter volume (GMV) difference between two groups. Results: Treatment non-responding patients showed significantly decreased GMV in the right orbitofrontal cortex (OFC) and left posterior cingulate cortex (PCC) compared with treatment responding patients (uncorrected p<0.001) The area of which GMV was larger in treatment non-responding patients than in treatment responding patients was right inferior temporal cortex (uncorrected p<0.001). In treatment non-responding group the GMV of right OFC and the improvement of Y-BOCS total score showed significant positive correlation (Kendall s tau-b correlation coefficient=0.310, p=0.019). 39

50 Conclusion: The baseline GMV reductions of the right OFC and left PCC and the positive correlation between the GMV of right OFC and the improvement of Y-BOCS total score in treatment non-responding OCD patients compared with treatment responding patients suggest the possibility that the structural abnormality of OFC and PCC at baseline can be used as neuroanatomical markers to predict the treatment response in OCD patients Keywords: obsessive-compulsive disorder, treatment response, refractory, voxel-based morphometry, orbitofrontal cortex, posterior cingulate cortex Student Number: