online ML Comm 생물정신의학 Vol. 16, No. 3, August 29 원저 병적도박환자에서의회백질부피변화분석 : 화소기반형태분석방법을이용한예비연구 최정석 1)2) 신영철 3) 정위훈 4) 정명훈 1) 장준환 1) 강도형 1) 최치훈 5) 권준수 1)4)6) 이준영 1)2) Gray Matter Changes in Patients with Pathological Gambling: A Preliminary Study Using Voxel-Based Morphometry Study Jung-Seok Choi, M.D., 1)2) Young-Chul Shin, M.D., Ph.D., 3) Wi Hoon Jung, M.S., 4) Myung Hun Jung, M.D., 1) Joon Hwan Jang, M.D., 1) Do-Hyung Kang, M.D., Ph.D., 1) Chi-Hoon Choi, M.D., 5) Jun Soo Kwon, M.D., Ph.D., 1)4)6) Jun-Young Lee, M.D., Ph.D. 1)2) ABSTRACT O bjectives:the purpose of this study was to examine structural abnormalities of brain in patients with pathological gambling(pg) using voxel-based morphometry. Methods:We compared gray matter(gm) volumes between 1 patients with PG and 14 age- and IQmatched healthy controls and examined the relationship of GM volumes with clinical variables in patients with PG. Results:We found significant increase of GM volume in the superior, middle, and inferior frontal gyri, the midbrain, the middle temporal gyrus, the precuneus, and the fusiform gyrus of patients with PG. A significant decrease of GM volume was observed in the parahippocampal gyrus and the lingual gyrus of the patient group. In addition, GM volumes in some of these regions were positively associated with South Oaks Gambling Screen score and negatively with age of onset in patients with PG. 1) 서울대학교의과대학정신과학교실 Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea 2) 서울특별시보라매병원신경정신과 Department of Neuropsychiatry, SMG-SNU Boramae Medical Center, Seoul, Korea 3) 성균관대학교의과대학강북삼성병원정신과학교실 Department of Psychiatry, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, Korea 4) 서울대학교뇌과학협동과정 Interdisciplinary Program in Brain Science, Seoul National University, Seoul, Korea 5) 국립의료원영상의학과 Department of Radiology, National Medical Center, Seoul, Korea 6) 서울대학교자연과학대학뇌인지과학과 Brain & Cognitive Science-WCU program, College of Natural Science, Seoul National University, Seoul, Korea 교신저자 : 이준영, 156-77 서울동작구보라매길 39 전화 ) (2) 87-2462 전송 ) (2) 87-3866, E-mail) benji@snu.ac.kr - 19 -
Conclusion:Current findings indicate that structural abnormalities in the fronto-temporal cortex, the midbrain, and the precuneus might be involved in the pathophysiology of PG, and contribute to some of the behavioral changes observed in patients with PG. KEY WORDS:Pathological gambling Voxel-based morphometry. 서론 병적도박 (pathological gambling) 은여러가지의부작용을야기함에도불구하고반복적인도박행동을특징으로하는만성적인정신질환이다. 1) 병적도박은몇가지의정신질환과특징을공유하는것으로기술되고있다. 반복행동에대한자기조절능력저하, 강박적인반복행동, 그리고행동이전의갈망등의양상을나타내어물질중독과유사한특징을보인다. 2) 또한병적도박의정신과적공존질환, 3) 유전적취약성, 4)5) 그리고치료에대한반응 6) 과같은임상적특징도물질중독과유사하여행위중독으로분류되기도한다. 2)7) 반면에도박행동이스스로조절하기어렵고일시적으로긴장이나불안을줄여주는등의측면은강박증에서의강박행위와유사하여강박관련장애로간주되기도하고, 8) DSM-IV 에서는충동조절장애의일종으로분류하고있다. 이렇듯병적도박의임상적측면으로는어느하나의질환군으로결정짓기에는일관된연구결과가부족한실정이다. 최근에는신경생물학적인연구를통해병리기전을밝히고특징을규명하려는시도들이많아지고있다. 물질중독에서의구조적뇌영상연구는상대적으로많이이루어져왔다. Mechtcheriakov 등 9) 은알코올중독환자에서전두엽, 섬이랑 (insula), 해마 (hippocampus), 시상 (thalamus), 그리고소뇌 (cerebellum) 의회백질 (gray matter) 부피감소를보고하였고 Franklin 등 1) 은코카인중독에서안와전두엽 (orbitofrontal gyrus), 띠이랑 (cingulate gyrus), 섬이랑과측두엽의회백질부피가저하되었다고하였다. 즉, 물질중독에서는주로전두- 변연계의구조적이상이보고되어왔다. 강박관련장애의뇌영상연구는주로강박증위주로진행되고있으며전두- 선조체-시상회로 (fronto-striato-thalamic circuit) 의이상이강박증에서나타나고있다. 11) 최근 Chamberlain 등 12) 은강박관련장애에속하는 발모광 (trichotillomania) 환자에서회백질부피의이상을보고하였다. 행동학습 (habit learning), 인지와정서조절등에관여하는뇌영역들, 즉선조체, 편도 -해마복합체 (amygdalo-hippocampal formation), 전두엽을포함한여러대뇌피질영역에서발모광환자의회백질부피가정상대조군에비해증가하였다. 발모광에서의뇌부피증가는물질중독에서의뇌영상결과와는상반되는것이었다. 현재까지병적도박환자를대상으로이루어진구조적뇌영상연구는보고되지않고있다. 본연구에서는용적화소에기초한형태분석 (voxel-based morphometry, 이하 VBM) 을이용하여물질중독과강박관련장애와구별되는병적도박환자들의구조적뇌이상을살펴보고자한다. 방법 1. 연구대상본연구에는일대학병원의외래클리닉에서 Structured Clinical Interview for DSM-IV( 이하 SCID) 13) 를이용하여병적도박으로진단받은 1명의남자환자 (28.3±3.92 세 ) 와나이와 IQ로짝진 14명의정상대조군 (25.29±4.7 세 ) 이참여하였다. 병적도박의진단과평생도박행동 (lifetime gambling activity) 의평가를위해 South Oaks Gambling Screen( 이하 SOGS) 14) 도추가적으로시행되었으며 5점이상인경우진단가능하도록하였다. 두그룹간에교육수준에는유의한차이가없었으며 1명의병적도박환자를제외한모든대상자는오른손잡이였다. 병적도박증상의심각도평가는 Yale-Brown Obsessive Compulsive Scale modified for pathological gambling( 이하 PG-YBOCS) 15) 로이루어졌다. 대상군제외기준은다음과같다 :1) 심각한두부손상의병력이있는경우, 2) 약물남용이나경련성질환의병력, 3) 정신병적증상의병력이있는경우. - 191 -
정상대조군은이전에어떠한정신과적질환의병력도없는경우에본연구에참여가능하였다. 모든연구대상자들은정신과약물복용력이없었으며 The Wechsler Adult Intelligence Scale( 이하 K- WAIS) 한국어판을이용하여 IQ를측정하였다. 본연구는강북삼성병원의의학윤리위원회 (institutional review board) 의윤리및안전지침과헬싱키선언을준수하며진행되었고모든대상자들에게연구참여전에연구내용과방법에대해설명한후서면동의서를받았다. 2. 뇌영상획득 (Image acquisition) 및처리자기공명영상은 1.5-T scanner(siemens, AVANTO, Erlangen, Germany) 를사용하였으며고해상도의해부학적영상을위해연속적인.9mm 두께의시상면 T1 강조영상을 magnetization prepared rapid gradient echo( 이하 MPRAGE) sequence(tr 116ms, TE 4.76 ms, FOV 23 23mm, FA 15, 28slices,.45.45.9 mm 3 ) 기법으로촬영하였다. 모든자기공명영상자료는뇌영상처리프로그램인 ANALYZE version 7.(Mayo Foundation, New York, USA) 을이용하여전교련 (anterior commissure)- 후교련 (posterior commissure) 선을중심으로위치조정하였다. Statistical Parameter Mapping, version 2( 이하 SP- M2) (Math-Works, Natick, MA, USA) 에서제공하는 152명의평균영상인 Montreal Neurological Institute tem-plate(mni, Montreal, Canada) 에병적도박환자와정상대조군의뇌영상을공간정규화 (spatial normalization) 한후평균영상을만들었다. 이평균영상을 8-mm 의 full width half maximum( 이하 FWHM) 을갖는가우시안커널 (Gaussian kernel) 로중첩적분하여편평화 (smoothing) 하였다. 이렇게생성된연구특정표준판에각각의원래영상을공간정규화하였고공간정규화된영상을 2. 2. 2.mm 3 의최종화소단위로변환하였다. 그리고, SPM2 에내재된프로그램으로회백질, 백질, 그리고뇌척수액으로분할하였다. 각각의영상을특정표준판에비선형적인방법으로공간정규화하는매트릭스를이용하여국소부피확장과수축을반영하도록 Jacobian determinant 를구하여이를각회백질영상에곱하였다. 변조과정을거친영상을 12-mm 가우시안커널로중첩 적분하여편평화하였다. 본연구에서는회백질영상이 VBM 을이용하여분석되었다. 3. 통계분석병적도박환자군과정상대조군간의인구학적변수의비교는연구대상자수가적기때문에 Mann-Whitney U test 를이용하여분석하였으며, 회백질부피차이는 SPM2내의 t-test(p<.1, uncorrected) 로분석하였다. 최소화소의크기는 25화소로하였으며나이와두개내부피 (intracranial volume, 이하 ICV) 의영향을통제하였다. 그리고환자군내에서의회백질부피와임상변수와의상관성을분석하기위하여 simple regression 을사용하였다. 결과 1. 인구학적특징과임상변수병적도박환자군과정상대조군의인구학적특징과임상변수는표 1에제시되어있다. 두연구대상군간에연령, 교육수준, 그리고 IQ 등의인구학적특징은유의한차이가없었다. 2. 전반적인부피비교 ICV 의경우병적도박환자는 1865.98±148.25mL, 정상대조군은 1811.86±125.73mL로두그룹간통계적유의한차이는보이지않았다 (t=-.965;p=.345). 또한회백질, 백질그리고뇌척수액의부피도병적도박과정상대조군간유의한차이가없었다 ( 회백질, 781.28± 65.36mL vs. 739.±5.5mL, t=-1.797, p=.86 ; 백질, 456.54±28.47mL vs. 454.32±35.25mL, t= -.164, p=.871; 뇌척수액, 628.15±67.53mL vs. 618.53±6.24mL, t=-.367, p=.717). 3. 회백질의국소분포차이의비교병적도박환자와정상대조군의공통의회백질감소및증가부위를영상이미지로변환한뒤, 통계적으로의미있는차이를보이는부위를결과로나타내었다 ( 표 2, 그림 1). 병적도박환자에서우측상전두이랑 (superior frontal gyrus), 좌측중간전두이랑 (middle frontal gyrus), 좌우측하전두이랑 (inferior frontal gyrus), 좌측중간측두이랑 (middle temporal gyrus), 좌우측쐐기앞 - 192 -
Table 1. Demographic and clinical characteristics the subjects Variables Control(N=14) PG(N=1) p* Demographic data Age(years) 25.29(4.7) 28.3(3.92).8 Education(years) 14.14(1.23) 14.9(1.85).22 IQ score 112.43(1.2) 111.8(11.89).93 Clinical data Age of onset(years) 26.2(4.16) - Duration of illness(years) 2.14(1.14) - PG-YBOCS - Total score 15.8(7.9) Obsession score 8.4(3.86) - Compulsion score 7.4(4.17) - SOGS 15.9(1.73) Data are given as mean(sd). *:Statistical significance test was done by Mann-Whitney U-test. PG:pathological gambling, IQ:intelligence quotient, PG-YBOCS:Yale-Brown Obsessive Compulsive Scale modified for pathological gambling, SOGS:South Oaks Gambling Screen Table 2. Gray matter changes in patients with pathological gambling compared with healthy controls Regions Decrease L/R MNI coordinates x y z Z-value BA p Lingual gyrus R -2-66 -1 3.46 19 <.1 Parahippocampal gyrus L -27-57 - 3.45 3 <.1 Increase Superior frontal gyrus R -26-71 -6 3.55 1 <.1 Middle frontal gyrus L -24-65 -25 3.51 1 <.1 Inferior frontal gyrus R -51-6 -18 3.49 44 <.1 L -54-2 -28 3.33 9 <.1 Middle temporal gyrus L -58-5 -3 3.25 21 <.1 Precuneus R -6-82 -41 3.33 7 <.1 L - -7-48 3.71 7 <.1 Fusiform gyrus R -44-47 -16 3.24 37 <.1 Midbrain L -3-13 -13 3.35 <.1 Clusters showing a spatial extent of at least 25 contiguous voxels, p<.1, uncorrected, are reported. R:right, L:left 소엽 (precuneus), 우측방추이랑 (fusiform gyrus) 그리고좌측중뇌 (midbrain) 의회백질부피가정상대조군에비해유의하게증가되었다. 반면에우측혀이랑 (lingual gyrus) 과좌측해마옆이랑 (parahippocampal gyrus) 에서는병적도박환자에서회백질부피의감소가관찰되었다. 4. 회백질부피와임상변수와의상관관계본연구에서는도박중독환자에서회백질의부피와임상변수 (SOGS 점수, PG-YBOCS 총점수, 발병연 령 ) 와의상관관계에대해서분석하였다. 병적도박환자의 lifetime gambling activity를반영하는 SOGS 점수는다음영역에서의회백질부피와양의상관관계를보였다 (at p<.1, uncorrected, k>25): 좌측상전두이랑 [51 화소, Z-max=4.38, coordinate(x, y, z)= -24, 9, 57], 좌측중간전두이랑 [125 화소, Z-max= 3.42, coordinate(x, y, z)=-26, -1, 55], 우측하전두이랑 [1573 화소, Z-max=3.51, coordinate(x, y, z)= 35, 26, ], 좌우측쐐기앞소엽 [ 좌측, 869 화소, Z- max=3.44, coordinate(x, y, z)=-3, -73, 32; 우측, - 193 -
A 4 4 3 3 2 2 B 1 Fig. 1. Brain regions with significant differences in gray matter volume in pathological gambling group(n=14) compared to healthy controls(n=1), superimposed on coronal slices of an average gray matter template and highlighted in yellow color scale(increase) and blue color scale(decrease)(p<.1, uncorrected for multiple comparisons, k>25 voxels)(a). Note that significant increases of gray matter volume are identified in the midbrain(b) and the right inferior frontal gyrus(c). The color scale shows t values for each significant voxel. C 1 1235 화소, Z-max=4.51, coordinate(x, y, z)=2, -7, 46], 그리고우측섬이랑 [insula, 1573 화소, Z- max=3.39, coordinate(x, y, z)=38, 12, 2]( 그림 2). 반면에 SOGS 점수와음의상관관계를보인영역은없었다. 현재의병적도박의심각도를반영하는 PG-YBOCS 총점수에서는회백질부피와상관관계를보이는영역은나타나지않았다. 발병연령과회백질부피사이에음의상관관계를보인뇌영역들은다음과같다 : 좌측중간전두이랑 [4343 화소, Z-max=4.79, coordinate(x, y, z)=-43, 19, 29], 우측하전두이랑 [9957 화소, Z- max=4.3, coordinate(x, y, z)=59, 33, 9], 전측띠이랑 [anterior cingulate, 996 화소, Z-max=5.17, coordinate(x, y, z)=-11, 35, 28], 좌측하두정엽 [843 화소, Z-max=4.48, coordinate(x, y, z)=-43, -46, 41], 우측쐐기앞소엽 [932 화소, Z-max=4., coordinate(x, y, z)=14, -53, 42], 좌우측중간후두이랑 ( 좌측, 125 화소, Z-max=3.68, coordinate(x, y, z)= -39, -73, 2; 우측, 2129 화소, Z-max=4.3, coordi- - 194 -
Positive correlation between gray matter volume and SOGS score A.8 12 1 8 6 4 2 Superior frontal cortex Response at (-24, 9, 57).6.4.2 -.2 -.4 -.6 -.8 Fitted Plus error 13 14 15 16 17 18 19 2 SOGS score Negative correlation between gray matter volume and age of onset B.25 15 1 5 Response at (-43, 19, 29).2.15.1.5 -.5 -.1 Fitted Plus error 14 16 18 2 22 24 26 28 3 32 Middle frontal cortex Age of onset Fig. 2. Significant correlations between gray matter volume and clinical variables in patients with pathological gambling. A:Positive correlation between gray matter volume in the left superior frontal cortex and South Oaks Gambling Screen(SOGS) score in the pathological gambling group(n=1). B:Negative correlation between gray matter volume in the left middle frontal cortex and age of onset in the pathological gambling group(n= 1). Results are superimposed on an average gray matter template and shown at p<.1 uncorrected and minimum cluster size of 25 voxels. nate(x, y, z)=52, -75, -16), 그리고우측섬이랑 [56 화소, Z-max=3.59, coordinate(x, y, z)=33, -7, 25]( 그림 2). 즉, 발병연령이빠를수록위영역에서의회백질부피가더큰것이다. 발병연령과양의상관관계를보인영역은좌측후두엽의쐐기이랑 [cuneus, 246 화소, Z-max=4.15, coordinate(x, y, z)=, -8, 5] 이었다. 고찰 이번연구에서는병적도박환자의전두엽내의여러영역, 측두엽, 쐐기앞소엽, 그리고중뇌에서회백질부피 의증가가관찰되었고해마옆이랑과혀이랑에서회백질부피의감소가나타났다. 또한병적도박환자에서회백질부피의증가는 SOGS 점수와양의상관관계를, 발병연령과는음의상관관계를보였다. 이번연구결과는병적도박의뇌구조적이상에대한최초의보고이다. 본연구에서는정상대조군에비해병적도박환자의전두엽과중뇌의회백질부피증가가두드러졌다. 전두엽은다양한고위인지기능에관여한다. 16) 의사결정 (decision making) 능력의손상과반응억제 (response inhibition) 기능의저하같은실행기능 (executive function) 의이상이병적도박환자들에서보고되어왔으며, 17-19) 이러한실행기능의이상은전두엽의구조적및기능적 - 195 -
이상과연관될수있다. 병적도박환자에서보이는 Iowa gambling task 같은의사결정능력평가에서의이상은장기간의이익보다는순간적인이익에더의미를두어서결국은손해를야기하는행동양상을일으키게된다. 2) 또한반응억제기능의이상은부정적인결과를야기함에도불구하고지속적으로같은행동을반복하게되는, 즉병적도박환자들의반복적인도박행동과관련될수있다. 19) 이처럼이번연구에서나타난전두엽영역에서의회백질부피이상은병적도박환자들의특징적인행동양상에부분적으로기여할수있을것이다. 회백질부피의증가는신경세포의크기증가나뇌신경발달상 (neurodevelopmental) 의적절한가지치기과정 (pruning process) 의이상, 또는다른병태생리적변화를반영하는것으로볼수있다. 여러대뇌피질영역의회백질부피증가는강박증이나발모광같은강박관련장애에서보고되었다. Chamberlain 등 12) 은발모광환자에서의회백질부피증가를정상적인신경발달과정에서의이상또는반복적인행동으로인한뇌영역의신경가소성변화 (neuroplastic change) 로해석하였으며 Yoo 등 21) 은강박증에서의회백질부피증가를다른뇌영역의이상에대한보상적변화 (compensatory change) 라고보았다. 본연구에서의전두엽회백질부피는 lifetime gambling activity 의정도가심할수록, 그리고발병연령이빠를수록더큰것으로보아전두엽회백질부피증가는병적도박환자들이보이는반복적행동양상과연관된뇌신경가소성변화로인한것을고려해볼수있을것이다. 하지만본연구는예비연구로써연구대상자의수가적기때문에다른영향에의한회백질변화를배제할수는없으며좀더명확한결론을내리기위해서는지속적인확장연구가필요할것이다. 중뇌의회백질부피증가도이번연구에서관찰된두드러진소견중하나이다. 중뇌는 dopaminergic mesolimbic circuit 을구성하는중요한부위이며도파민생성과관련되어있다. 22)23) 중독의병태생리에중요한역할을하는도파민은보상 (reward) 및강화행동과밀접한연관성을가지고있으며병적도박환자들이보이는반복적인도박행동은보상기전의이상과관련된다. 24) 약물중독환자들에서약물로인해도파민분비가증가되고이는기분의변화와연관된다는기존의연구결과들처럼 25) 병적도박환자들에서보인중뇌의회백질부피증가는보상기전과관련된도파민분비이상을시사하 는것이라고볼수있다. 반면본연구에서는해마옆이랑의부피감소가관찰되었다. 니코틴중독환자들에게중독관련자극을보여주었을때해마옆이랑의활성화정도가자극으로인한갈망도 (cue-elicited craving) 와상관성을보인다는연구결과 26) 와알코올중독환자에서즉각적인보상과해마옆이랑의뇌활성화정도가상관성을보이는것으로보아 27) 물질중독의병태생리에해마옆이랑이관여한다는것을알수있다. 이번연구에서처럼행위중독의일종인병적도박에서관찰된해마옆이랑의부피감소는중독환자에서보이는기억및보상기전이상에해마옆이랑이관여함을시사한다고하겠다. 이러한본연구의결과는약물중독이나강박관련장애에서관찰된뇌회백질이상과는구별되는특징이있다. 약물중독환자들에서는전두- 변연계영역들의회백질부피감소가두드러지고 9)1) 강박관련장애환자들은전두-선조체영역들의구조적이상을나타냈다. 11)12) 반면에병적도박환자에서는전두- 측두엽과중뇌의회백질부피증가가주로관찰되었다. 특히전두엽과중뇌의구조적이상은병적도박의병태생리를나타내는특징적인소견이라할수있다. 본연구의제한점은다음과같다. 첫째, 남자환자들만을대상으로하였고연구대상자수가적기때문에이번결과를일반화하기에는무리가있다. 하지만, 보상기전에대한뇌의남녀의차이가있기때문에 28) 남자환자들을대상으로한본연구는연구대상군의동질성을위해의미가있을것이다. 둘째, 화소기반형태분석방법자체의특성이다. 공간정규화시에뇌구조물들의왜곡된변화나편평화과정의커널크기의선택등여러가지교란변수가있을수있으나인위적인구획설정없이전체적인뇌부위의변화를확인할수있는장점이화소기반형태분석방법을적용하기에의미가있을것으로생각된다. 결론적으로, 본연구는병적도박환자의전두엽과중간측두엽, 두정엽의쐐기앞소엽, 그리고중뇌에서유의한회백질의부피증가소견을증명하였고이는물질중독과강박관련장애의뇌구조적이상과는구별되는특징이었다. 앞으로병적도박환자의뇌이상을규명하기위해서더많은연구대상군확보와추적연구가필요할것이다. - 196 -
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