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1 대한임상신경생리학회지 10(1):13~24,2008 ISSN 편두통의기능적뇌영상 고려대학교의과대학신경과학교실 Functional Neuroimaging in Migraine Ji Hyun Kim, M.D. Department of Neurology, Korea University College of Medicine, Seoul, Korea Recieved 10 June 2008; accepted 13 June 2008 Functional neuroimaging, especially positron emission tomography (PET) and functional magnetic resonance imaging (MRI), is the main tool that allows the unveiling of the neurovascular events during a migraine attack. In migraine with aura, functional neuroimaging has contributed greatly to the understanding of the fundamental pathophysiology of the visual aura, whereas in migraine without aura, the PET findings of brainstem activation suggest a pivotal role of brainstem in the generation of migraine headache. In addition, voxel-based morphometry (VBM) method has provided an insight into the morphometric changes of the brain, which might be considered as a consequence of repeated migraine attacks. In this article, I will briefly discuss the main neuroimaging findings pertaining to the pathophysiology of migraine. Key Words: Migraine, Single photon emission computed tomography (SEPCT), Positron emission tomography, Blood oxygen level dependent (BOLD) MRI, Voxel-Based morphometry (VBM) 서 론 편두통은흔한일차두통증후군으로서박동성통증이반복적으로주로머리의한쪽에서일어나는것이특징이며대부분 4시간에서 72시간동안지속되고두통이외에메스꺼움, 구토, 빛공포증또는소리공포증등의증상이동반된다. 1 편두통은일종의신경혈관성두통 (neurovascular headache) 으로일차적으로뇌의반복적인기능이상으로발생한다고이해하고있다. 2 과거에 CT와 MRI를 Address for correspondence; Ji Hyun Kim, M.D. Department of Neurology, Korea University Medical Center, Korea University College of Medicine 80 Guro-dong, Guro-gu, , Seoul, Korea Tel: Fax: jhkim.merrf@gmail.com 이용하는전통적인구조적뇌영상 (structural neuroimaging) 기법으로는편두통발작기에발생하는뇌의기능적변화를관찰하기불가능하기때문에일시적, 반복적으로발생하는편두통의기본적인병태생리를이해하기어려웠다. 그러나최근 10년동안기능적뇌영상 (functional neuroimaging) 기술의발달로편두통의병태생리학적기전을이해하는데혁신적인발전이있었다. 즉, PET, SPECT 그리고 blood oxygen-level dependent (BOLD) 신호의변화를관찰하는기능적자기공명영상 (functional MRI, fmri) 등의뇌영상기술을이용하여편두통조짐시기또는두통발작기에일시적으로발생하는뇌혈류의국소적인변화를관찰함으로써편두통의병태생리가상당히밝혀졌다. 3-7 다음에서삼차신경혈관계 (trigeminovascular system) 와이와관련된편두통의병태생리를간단히알아보고현재까지보고되어있는편두통의기능적뇌영상연구결과들을살펴보기로한다. Copyright 2008 by The Korean Society for Clinical Neurophysiology 13

2 본론 1. 삼차신경혈관계와병태생리삼차신경은다섯번째뇌신경으로감각신경과운동신경으로구성되어있다. 이중감각신경은얼굴, 이마, 부비동, 코와입의점막, 뇌혈관, 경질막등에서발생되는통각, 온도감각, 촉각을담당하는고위중추로전달하며편두통의병태생리에중추적인역할을한다. 삼차신경의감각섬유를내는세포체는가단극신경원 (pseudounipolar neuron) 으로두개내의삼차신경절에위치한다. 이들세포의말초섬유는삼차신경의세가지분지 (V1; ophthalmic, V2; maxillary, V3; mandibular) 를구성한다. 8 이세분지는얼굴, 이마, 구강에서각각감각을담당하는부위가명확히구분된다. 삼차신경의세분지모두경질막에신경을분포시키며뇌줄기 ( 교뇌, 연수 ) 로들어가삼차신경주감각핵 (principal sensory nucleus) 에서연접하거나삼차신경척수로 (spinal trigeminal tract) 로들어가교뇌, 연수, 상위경수내의삼차신경척수핵 (spinal trigeminal nucleus) 에서연접한다. 8 삼차신경은뇌혈관과경질막에분포하는유일한신경이며삼차신경의가단극신경원에의해뇌혈관에신경이분포되어있고이들세포체는삼차신경절에분포하여삼차신경혈관계 (trigeminovascular system) 를형성한다. 9 삼차신경혈관계의말초성섬유는두개혈관가까이에서연접하고중추성섬유는뇌줄기하부와경수상부에서연접한다. 이들삼차신경혈관계의중추성또는말초성섬유들은두개혈관에서발생하는통증의신호를통각을담당하는뇌중추로전달하는역할을한다 (Fig. 1). 편두통은신경혈관성두통이며삼차신경혈관계의주기적인기능이상에의해발생한다고알려져있다. 2,9 기존의연구들에의하면편두통의일차적인기능이상은혈관긴장도와통각을조절하는뇌줄기에서발생한다. 이뇌줄기중추의기능이상으로삼차신경의감각섬유에의해신경분포되는두개혈관이확장된다. 10 확장된혈관은혈장단백의혈관외유출을유도하고신경인성염증을촉진시키며뇌수막의통각수용기 (nociceptors, 뇌수막에분포하는삼차신경의감각섬유 ) 를활성화시킨다. 활성화된삼차신경의감각섬유는통증에대한반응을뇌줄기로전달하며뇌줄기에서시상, 일차감각겉질과같은고위중추로도전달된다. 또한삼차신경섬유에서 substance P와 calcitonin gene-related peptide 같은혈관활성물질들 (vasoactive substances) 이유리되어혈관확장과신경인성염증반응을악화시키며결국이과정에서삼차신경절의신경세포 가활성화되어통증자극이뇌로전달된다. 편두통이진행함에따라삼차신경에서통증자극을일차로받는뇌줄기와척수의중추는감작되어두통이심해지고환경적또는무통자극에도민감하게반응하게되어피부무해자극통증 (cutaneous allodynia) 이발생할수있다. 11,12 2. 조짐약 15% 정도에서편두통은시각조짐 (visual aura) 현상이선행하는데전형적으로는지그재그형태의선이한쪽시야에서서서히움직인다 년에 Lashley는자신의편두통에선행하는암점을동반하는시각조짐현상을기술하면서이는어떤이상이시각겉질에서 3~5 mm/ minute 의속도로확산되면서발생하는증상이라고제안하였다. 14 뒤이어신경생리학자인 Leao 는동물실험에서화학적또는기계적자극을주면대뇌겉질이과흥분하고뒤이어억제현상이나타났으며이현상은 3~4 mm/ minute 의속도로대뇌겉질에서확산되는것을보고하면서이를겉질확산성억제 (cortical spreading depression, CSD) 라고명명하였다. 15 겉질확산성억제현상이편두통에선행되는시각조짐과확산되는속도가비슷하다는점에서시각조짐을일으키는기전으로제시하였고, 16 이를임상적그리고전기생리학적으로뒷받침하는동물실험결과들이발표되었다. 17,18 이가설에의하면시각조짐중에발생하는뇌혈류의감소는비정상적인기능을가진신경세포로인해대사요구가감소되어나타나는결과이고시각조짐을유발하는일차적인원인은아니라고할수있다. 지난 20 년간발표된기능적뇌영상을이용한연구들이이이론을점차확고히뒷받침하고있다. 네가지의다른뇌영상기술이편두통의시각조짐현상을연구하는데적용되었다. 즉, 1) PET, SPECT, perfusion-weighted MRI (PWI) 를이용하여뇌혈류의변화를관찰하는방법, 2) diffusionweighted MRI (DWI) 를이용하여세포막의정상적인삼투압기울기 (osmotic gradient) 를유지하는신경세포의생존도를평가하는방법, 3) blood oxygen-level dependent (BOLD) MRI 를이용하여생리적인자극에신경세포가반응하는정도를보는방법그리고 4) magnetic resonance spectroscopy (MRS) 를이용하여신경세포의대사기능에대한정보를알아내는방법등이다. 다음에서상기네가지영상기술을이용하여편두통에동반되는시각조짐현상을관찰한연구들을알아본다. 1) 조짐기의뇌혈류연구 (Blood flow studies in aura) 1980년대초에 Olesen 과 Lauritzen 등은경동맥혈관조 14 Korean J Clin Neurophysiol / Volume 10 / June, 2008

3 편두통의기능적뇌영상 Figure 1. Migraine involves dysfunction of brainstem pathways that normally modulate sensory input. The key pathways for the pain are the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex. These neurons, in turn, project through the quintothalamic tract, and after decussating in the brain stem, form synapses with neurons in the thalamus. There is a reflex connection between neurons in the pons in the superior salivatory nucleus, which results in a cranial parasympathetic outflow that is mediated through the pterygopalatine, otic, and carotid ganglia. This trigeminal autonomic reflex is present in normal persons and is expressed most strongly in patients with trigeminal autonomic cephalgias, such as cluster headache and paroxysmal hemicrania; it may be active in migraine. Brain imaging studies suggest that important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus ceruleus, and nucleus raphe magnus. Reproduced with permission from the New England Journal of Medicine. 2 영술을통해 133 Xe를주입하고시각조짐이있을때국소뇌혈류 (regional cerebral blood flow) 가한쪽대뇌반구의뒷부분에서감소됨을증명하였다. 19,20 시각조짐중에감소된국소뇌혈류는한시간까지감소된상태로지속되었으며한시간이지나서뇌혈류는정상화되거나혹은여전히국소적으로감소된상태로남아있었다. 21,22 이연구에서측정한뇌혈류의감소정도는 17~35% 19,21 로뇌허혈을유발할수있는정도는아니므로 oligemia ( 혈량감소증 ) 라고명명하였다. 또한이연구들에서조짐증상중에발생한 oligemia 가뇌혈관영역을따르지않고점차뇌의앞쪽으로퍼지는현상이관찰되었는데이를 spreading oligemia 라고하였다. 20 다른한연구에서는뇌혈류변화의크기와지속시간이시각조짐의정도와발생시간과상관관계가있음을보고하면서관찰된뇌혈류의감소가편두통의조짐증상을유발하기에충분하다는것을제시하였다. 23 그러나상기연구들에서몇몇환자들은시각조짐이있을 때뚜렷한뇌혈류의변화가없었으므로 20,21,23 SPECT 로측정하는뇌혈류의변화를일반화하기에는다소부족함이있다. 위에서열거한 SPECT 를이용한연구들은처음으로편두통환자들의시각조짐에동반되는뇌혈류의변화를관찰했다는점에서매우혁신적이며편두통연구에선구자적인역할을했으나초창기 SPECT 의시간적, 공간적해상력의한계점이문제로지적된다. PWI 는혈관으로주입된상자성조영제 (gadolinium) 에의해서발생하는뇌실질내신호소실의측정을통하여뇌관류의변화를관찰하는 MRI 기법으로 relative cerebral blood volume (relcbv), relative cerebral blood flow (relcbf), mean transit time (MTT) 의세가지혈역학적변수들을측정할수있다. PWI는특히미세혈관 ( 모세혈관, 소동맥 ) 의변화에민감하고비침습적이며방사성동위원소를사용하는뇌영상기법보다공간적해상력이높다. Cutrer 등은편두통환자 4명의시각조짐에서 PWI 를하 Korean J Clin Neurophysiol / Volume 10 / June,

4 였는데시각증상이발생한시야의반대쪽후두엽에서 relcbf와 relcbv가평균 35%(16~53%) 와 19%(6~33%) 로각각감소하였으며 MTT 는평균 32%(10~54%) 로증가함을관찰하였다. 24 다른연구에서도 7명에서시각조짐이있을때 PWI를하였고시각증상의반대쪽후두엽겉질에서 relcbf 와 relcbv 가 27% 와 15% 로각각통계적으로유의하게감소하였고 MTT 는 32% 증가하였으며이러한변화는조짐이기를지나두통기에서 2.5시간까지지속되었다. 25 다른대뇌겉질과시상등의영역에서는의미있는혈역학적변화가관찰되지않았다. 24,25 이러한소견은앞서언급한 Olesen 등의 133 Xe SPECT 연구결과와일치하는소견으로후두엽겉질의뇌혈류감소또는혈관수축이반대쪽시야의시각조짐을유발한다는가설을입증해주는결과이다. 그러나최근에발표된한연구에서는지속적시각조짐또는시각증상이있었던 4명의 PWI 에서후두엽겉질의 relcbv, relcbf, MTT 의의미있는변화가관찰되지않았고이결과는편두통의시각조짐이후두엽의혈역학적변화외에다른요인으로도유발될수있다는것을의미한다. 26 H 15 2 O를추적자 (tracer) 로사용하는 PET 는반감기가 2 분정도로매우짧아순간적인뇌혈류의변화를관찰하는데용이하므로 brain activation 연구에주로사용된다. Woods 등은무조짐편두통을가진 21세여자에서시각자극으로두통을유발하고 15분간격으로 12회의 H 15 2 O PET 를하여뇌혈류의변화를관찰하였다. 27 양측성으로뇌관류저하 (hypoperfusion) 가시각겉질인 Brodmann s area 18, 19에서시작하여점차앞쪽으로이동하는현상을관찰하였고저자들은이현상이겉질확산성억제의결과라고제시하였다. 그러나이실험에서환자는시각조짐은유발되지않았고스크린의목표점을응시하는데약간의어려움만있었다고보고하였으므로이결과를전형적인시각조짐의기전으로제시되는겉질확산성억제의뇌혈류변화라고보기에는다소논란의여지가있다. 4 최근의한연구에서 glyceryl trinitrate 를주입하여시각조짐을유발하였고이때 12번의 H 15 2 O PET 영상을얻어분석한결과시각조짐 ( 지그재그섬광 ) 이발생한시야의반대쪽후두엽겉질 (Brodmann s area 17) 에서뇌혈류의증가가관찰되었다. 28 이는아마도시각조짐증상중에서뇌혈류의저하로발생한다고알려진음성증상 ( 암점 ) 보다는양성증상 ( 섬광 ) 을설명하는결과라고생각한다. 4 2) 조짐기의 DWI 연구 DWI 는세포막의 Na + /K + ATPase activity의손상으로 발생하는물분자의확산운동제한정도를평가하는뇌영상기법으로신호증가는전형적으로뇌경색에서관찰되나 29 겉질확산성억제의동물모델에서도관찰되었다 화학자극으로유발된겉질확산성억제의동물모델에서감소되는겉보기확산계수 (apparent diffusion coefficient, ADC) 의파형이평균 2.9 mm/min 의속도로퍼져나갔으며 ADC가감소된겉질영역은약 30초후에정상으로회복되는것이관찰되었다. 30 이는인간편두통의시각조짐에서동반되는뇌혈류의변화를관찰한 PWI, SPECT 연구결과를뒷받침해주며생리적연관성을제시한연구결과이다. 32 그러나 4명의환자에서시각조짐직후그리고두통기직전의 DWI 에서는의미있는 ADC 감소가관찰되지않았다. 24 또한지속적시각조짐시기의 DWI 에서도역시후두엽을포함한뇌의모든영역에서 ADC 감소는보이지않았다. 26 이는겉질확산성억제의동물모델에서관찰된 ADC 의변화와일치하지않는소견으로 DWI 가시각조짐시기에동반되는생리적인변화를찾아내는데충분한해상도와민감도를가지지못해서나타나는결과일수있다. 가족편마비편두통 (familial hemiplegic migraine) 환자에서조짐증상 ( 편마비 ) 이지속되는중의 DWI에서도의미있는신호변화가관찰되지않았다. 33 그러나비슷한가족편마비편두통환자에서편마비의조짐증상이발생한시기의 DWI에서 ADC 값이반대쪽대뇌반구에서감소하였고 36일째반복한 DWI 에서는 ADC 가감소된영역이감소했으며 3개월후에는정상으로회복된증례보고 34 도있어편두통조짐기에서 DWI 의역할에대해서는논란이있다. 3) 조짐기의 BOLD MRI 연구 BOLD MRI 는뇌모세혈관의혈류변화에따른 deoxyhemoglobin 농도의변화를 MRI신호로관찰하는영상기법으로시간적, 공간적해상력이뛰어나뇌의기능적활성화 (functional activation) 연구에가장많이사용되고있다. Cao 등은조짐편두통환자 10명과무조짐편두통환자 2명을대상으로시각자극을준후에후두엽에서 BOLD 신호를분석하였다. 35 이중 5명에서시각증상또는두통이유발되었고자극에의해유발된초기 activation 이시각증상직전에억제되는현상을관찰하였다. BOLD 신호가감소된부위는느린속도 (3~6 mm/min) 로인접한후두엽으로퍼져나갔으며, 이는편두통에서시각조짐또는두통이초기신경세포 activation 의 spreading depression과후두엽겉질의증가된산소화를동반한다는것을입증한의미있는연구결과이다. 35 Cao 등은후속연구에서시각자극으로시각조짐과두통을유발하여 BOLD 신호의 16 Korean J Clin Neurophysiol / Volume 10 / June, 2008

5 편두통의기능적뇌영상 Figure 2. Spreading suppression of cortical activation during migraine aura. (A) A drawing showing the progression over 20 min of the scintillations and the visual field defect affecting the left hemifield, as described by the patient (P.R.). The fixation point appears as a small white cross. The red line shows the overall direction of progression of the visual percept. The front of the scintillation at different times within the aura is indicated by a white line. (B) A reconstruction of the same patient s brain (P.R.), based on anatomical MR data. The posterior medial aspect of occipital lobe is shown in an inflated cortex format. In this format, the cortical sulci and gyri appear in darker and lighter gray, respectively, on a computationally inflated surface. MR signal changes over time are shown to the right. Each time course was recorded from one in a sequence of voxels that were sampled along the calcarine sulcus, in the primary visual cortex (V1), from the posterior pole to more anterior location, as indicated by arrowheads. A similar BOLD response was found within all of the extrastriate areas, differing only in the time of onset of the MR perturbation The MR perturbations developed earlier in the foveal representation, compared with more eccentric representations of retinotopic visual cortex. This finding was consistent with the progression of the aura from central to peripheral eccentricities in the corresponding visual field (A and C). (C) The MR maps of retinotopic eccentricity from this same subject, acquired during interictal scans. As shown in the logo in the upper left, voxels that show retinotopically specific activation in the fovea are coded in red (centered at 1.5 eccentricity). Parafoveal eccentricities are shown in blue, and more peripheral eccentricities are shown in green (centered at 3.8 and 10.3, respectively). Reproduced with permission from the National Academy of Sciences, U. S. A. 37 변화를측정하였는데후두엽겉질의변화직전에뇌줄기의적색핵과흑색질에서 BOLD 신호가증가하는현상을관찰하였다. 36 이는편두통에서시각조짐과두통이뇌줄기구조물의 activation 으로유발될수있다는가능성을제시한중요한연구결과이다. 36 Hadjikhani 등은조짐편두통환자 3명에서 BOLD 신호의변화를증상이없을때부터자발성또는시각자극으로발생된시각조짐기를거쳐두통기까지연속적으로관찰하였다. 37 시각조짐증상의초기에 BOLD 신호의증가가국소적으로선조외겉질 (V3a, extrastriate cortex) 에서관찰되었고이증가된 BOLD 신호는시각증상의 retinotopic presentation ( 망막대응 ) 과일치하게일차시각겉질과시각연합겉질로평균 3.5 mm/min 의속도로퍼져나갔 다. 이러한 BOLD 신호의증가는아마도혈관확장에서기인하는것으로생각하였다. BOLD 신호의증가직후에는망막대응과일치하는부위에서 BOLD 신호의감소가뒤따르는현상이관찰되었으며이는아마도초기혈관확장후에발생하는혈관수축으로발생하는것으로이해하고있다 (Fig. 2). 이는편두통의시각조짐이단순히후두엽겉질의국소적인허혈로발생하는것이아니고겉질확산성억제와같은전기생리학적인변화로발생한다는것을입증한중요한연구결과이다. 겉질확산성억제현상과 BOLD MRI 로관찰된편두통의시각조짐은다음과같은공통적인소견을갖는다. (1) 시각조짐과겉질확산성억제는 3~4.5 분간지속되는초기충혈 (hyperemia) 과연관이있다. (2) 시각조짐과겉질확산성억제에서의충혈은 60~120 분간지 Korean J Clin Neurophysiol / Volume 10 / June,

6 속되는경도의관류저하 (hypoperfusion) 가뒤이어나타난다. (3) 충혈과관류저하의복합된변화는후두엽겉질을따라 2~5 mm/min 의속도로퍼진다. (4) 시각조짐또는겉질확산성억제중에유발된시각반응은억제된후회복하는데 15분정도가소요된다. 이러한공통적인소견으로미루어 Leao 가처음관찰하여보고한겉질확산성억제현상이 15 인간편두통의시각조짐중에발생하는후두엽겉질의변화를가장잘설명해주는이론이라고생각된다. 4) 조짐기의 MRS 연구 MRS는뇌의대사물 (metabolite) 에관한생화학적인특성을관찰하는비침습적인영상기법으로특히기능적인관점에서보면신경세포의기능에관한유용한정보를제공한다. 1 H와 31 P의두원자를이용한방법이있는데 1 H MRS는 N-acetylaspartate, lactate, glutamate, aspartate, GABA, choline, myoinositol, creatine 등을측정하고 31 P MRS는세포내 ph, ATP 대사, phospholipids 대사에관한정보를제공한다. 현재까지시각조짐중의 MRS 연구는없다. 그러나 1980 년대말에 Welch 등은일련의 single-voxel 31 P MRS 연구에서, 두통기에겉질에서 phosphocreatine 이감소하고 inorganic phosphate 가증가하여결국뇌의 phosphorylation potential 의척도가되는 phosphocreatine/inorganic phosphate 비율이조짐편두통환자에서는감소하였으나정상대조군과무조짐편두통환자에서는의미있는변화가없음을확인하였다. 38 또한두통기에측정한세포내 ph는변화가없음을보고하면서편두통환자겉질의기능적변화는혈관수축으로인한허혈보다는대뇌겉질의호기성대사의장애에기인한다고주장하였다. 38,39 또한 Welch 등은연이은 MRS 연구에서조짐편두통환자의세포내 Mg 2+ 농도가낮고고에너지 phosphate 의대사전환이증가되어있음을확인하고이런변화로인해 N-methyl-D-aspartate (NMDA) 수용체의활성도가억제되지않아결국겉질확산성억제와같은겉질의흥분도가증가하여편두통이발생한다고주장하였다. 40 근래에더많은환자의두통비발작기 MRS 연구가발표되었는데조짐편두통과편마비편두통환자에서후두엽을포함한뇌의뒤영역의세포내 Mg 2+ 농도가대조군에비해낮은경향을보였고이러한소견은무조짐편두통환자에서는없었다. 41 이연구결과로부터신경학적결손 ( 예, 시각조짐, 편마비 ) 을동반하는편두통환자의뇌는비발작기에 Mg 2+ 농도가정상인보다낮고이로인해겉질의과흥분성이유도되어신경학적증상을유발하는반면무조짐편두통환자의뇌는 Mg 2+ 농도변화가없 으므로조짐증상을동반하지않는다는점을유추할수있다. 41 그러나 Lodi 등의연구에의하면비록조짐편두통환자의후두엽 cytosolic free Mg 2+ 농도가더낮았으나무조짐편두통환자도대조군보다 free Mg 2+ 농도가의미있게낮게측정되었으므로 Mg 2+ 농도변화의유무와편두통의유형별차이의상관성에대해서는논란이있다. 42 최근의 1 H MRS 연구에서는시각조짐만을가진편두통환자는시각겉질의 resting lactate 농도가증가되어있었고반복적인시각자극으로더이상의증가는관찰되지않았던반면시각조짐외에저림증, 불완전마비, 언어장애등의증상을추가로가진환자는 resting lactate 농도가대조군과차이가없었으나시각자극으로 lactate 농도가상승하는것을관찰하였다. 43 두그룹간에관찰된 lactate 농도변화의의미는불명확하나조짐편두통환자의시각겉질에서세포내미토콘드리아의기능장애가존재한다는것을제시한점에서연구의의미가있다. 다른 1 H MRS 연구에서는조짐편두통환자에서시각자극전의 N-acetylaspartate/ creatine 비율이무조짐편두통환자와대조군보다낮았고시각자극중에측정한 N-acetylaspartate 의감소정도가조짐편두통환자만의미있게감소하여조짐편두통환자의시각겉질의미토콘드리아기능이저하되어있을가능성을재차뒷받침하였다. 44 그러나다른연구들에서는조짐편두통환자의후두엽겉질과 45 백색질에서 46 측정한 N-acetylaspartate 농도에변화가관찰되지않아뇌의대사물변화또는대사장애와조짐편두통과의관계는아직정립되지않은상태이다. 3. 두통조짐편두통과는달리무조짐편두통에서는두통기에의미있는혈류변화가 SPECT 연구에서는관찰되지않았다. 21,22,47 Friberg 등은환자 10명의두통발작기와비발작기에각각 SPECT 를이용하여국소뇌혈류의변화와경두개도플러검사 (transcranial Doppler sonography) 를이용하여중간대뇌동맥의혈류속도를측정하였다. 48 비발작기의양쪽중간대뇌동맥의혈류속도와두통기에두통이없는대뇌반구의혈류속도는정상이었던반면두통기에두통이있는대뇌반구의중간대뇌동맥의혈류속도는의미있게저하되었고 sumatriptan 으로두통이사라진후에는혈류속도가정상으로회복되었다. 그러나두가지경우모두에서 SPECT 를이용하여측정한중간대뇌동맥영역의뇌혈류는변화가없었다. 48 상기결과를근거로저자들은두통은중간대뇌동맥의확장으로발생하고 5HT 1B/1D 수용체작용제인 sumatriptan 의혈관수축작용으로호전된다 18 Korean J Clin Neurophysiol / Volume 10 / June, 2008

7 편두통의기능적뇌영상 고주장하였다. 49,50 그러나뇌혈류에는변화가관찰되지않아중간대뇌동맥의확장이편두통의발병기전에기여하는역할은증명되지않은상태이다. 더구나이중맹검환자 -대조군교차연구에의하면 66명의두통기와비두통기에경두개도플러검사를이용하여측정한여러동맥들의혈류속도는통계적으로의미있는변화가없었으며 sumatriptan 의투여로중간대뇌동맥과기저동맥의뇌혈류속도는다소증가하는경향을보였으나이변화는두통완화시기와일치하지않았다. 51 이연구에서는혈관수축작용이두통을완화시키는 sumatriptan 의주된작용이라는가설을뒷받침하지못했다 년대중반부터 H 15 2 O PET 를이용하여두통기에국소뇌혈류의변화를관찰하는연구결과들이발표되기시작하였고일련의연구에힘입어무조짐편두통의두통발생기에관한혁혁한발전이이루어지게된다. 위에서언급한 Woods 등의연구는 27 무조짐편두통환자의두통기에 PET 를이용하여뇌혈류변화를관찰했다는점과처음으로양측성 spreading hypoperfusion 을규명했다는점에서주목을받는다. 그러나이결과는 SPECT 를이용하여무조짐편두통환자의두통기에측정한국소뇌혈류에는의미있는변화가관찰되지않았던연구와는상이하다. 21, 년에 Weiller 등이편두통의두통발생에관한매우중요한연구결과를발표하였다. 52 이연구에서는편두통환자 9명에서자발성편측두통이발생했을시기와 sumatriptan 으로두통을완화시킨후에각각 H 15 2 O PET를하였다. 두통기에 cingulate area, auditory cortex, visual association cortex 와두통과반대쪽상부뇌줄기 (rostral brainstem) 등에국소뇌혈류가의미있게증가되었고, sumatriptan 피하주사후의 PET 에서는 cingulate cortex, auditory cortex, visual association cortex에증가된뇌혈류는정상으로회복되었으나상부뇌줄기의뇌혈류는지속적으로증가되어있었다. 저자들은연구결과를바탕으로편두통의두통발생이진통 (antinociception) 을조절하는것으로알려진상부뇌줄기구조물의기능이상혹은 activation 과관계가있다는가설을처음으로제시했다. 52 즉, 상부뇌줄기구조물이편두통의두통발생에관여하는특이적영역이라는가설인데그이유는다음과같다. 뇌줄기의 activation 은비두통기에는없으며군발두통 53 또는이마부위에국소적으로 capsaicin 을주사한후편두통과유사한동통을유발한실험에서는뇌줄기의 activation 이관찰되지않은점등이다. 54 이가설은다른연구자가발표한후속연구들에의해입증되었다 년에 Bahra 등은무조짐편두통과군발두통의두가지일차두통 증후군을가지고있었던 43세남자에서 glyceryl trinitrate 로두통을유발하고두통기에 6회, 비두통기에 3회그리고 sumatriptan 주사후 3회의 H 15 2 O PET를각각하였다. 55 유발된두통은 International Headache Society (IHS) 의진단기준을 56 만족하는전형적인편두통이었고, PET 영상들을 statistical parametric mapping (SPM) 이라는영상통계처리방법을이용하여분석하였다. 두통기에얻은 PET 영상에서비두통기보다일반적인중추성통증전달에관여하는영역인 thalamus, insular cortex, prefrontal cortex 등과편두통특이영역인 dorsal rostral pons 에 activation을관찰할수있었다. 유발된두통은편두통이었고군발두통특이영역으로알려진시상하부에는 53 뇌혈류의증가가없었으므로 rostral pons 가편두통발생에관여하는특이영역임을입증하는중요한연구결과이다 년에 Afridi 등은무조짐편두통환자 3명과조짐편두통 2명에서자발성두통발작기에고해상도의 PET 를하여비발작기와비교하였다. 57 발작기에두통과같은쪽의 dorsal pons 의 activation 이관찰되었고, 이외에도 anterior cingulate gyrus, prefrontal cortex, insula 에도 activation 이보였는데이는이전연구결과와 52,55 잘일치하는소견이다. 57 위에서열거한연구들에의하면두통과같은쪽 pons 의 activation 이보고되었으나편측성을알아보기위한연구는아니었고또한연구에참여한환자가많지않았기때문에이들간의관계를정립하기에는부족하였다. Afridi 등은이에대한의문을가지고그들의후속논문에서두통과뇌줄기 activation 의편측성과의관계를발표하였다. 58 Glyceryl trinitrate 주입후오른쪽두통, 왼쪽두통, 양쪽두통이유발된환자각각 8명씩을선발하여 H 15 2 O PET 영상을분석하였는데오른쪽두통이유발된환자에서는오른쪽교뇌에, 왼쪽두통이유발된환자에서는왼쪽교뇌에, 그리고양쪽두통이유발된환자에서는왼쪽에치우쳐있기는하나양쪽교뇌에서뇌혈류증가소견이각각관찰되었다 (Fig. 3). 58 이는오랫동안풀리지않았던의문인편두통의편측성에관해새로운기능적-해부학적해답을제시한매우중요한연구결과이다. 일련의 PET 연구들에의해뇌줄기가편두통의특이적영역이고뇌줄기의 activation 이두통발생에관여한다는점은현재정설로받아들여지고있다. Triptan 계열의약물이개발되기전편두통발작치료의일차선택약으로널리쓰이던 dihydroergotamine 의결합부위가뇌줄기라는연구도편두통에서뇌줄기의역할을뒷받침하고있다. 59 그러나현재까지뇌줄기의어떤구조물이편두통의두통 Korean J Clin Neurophysiol / Volume 10 / June,

8 Figure 3. Activation of the ipsilateral pons in patients with right-sided attacks (n= 8, left panel) and left-sided attacks (n=8, right panel). Reprinted with permission from the Oxford University Press. 58 Figure 4. Statistical parametric maps (SPM) demonstrating regional differences in grey matter volume (GMV) between 20 migraine patients and 33 controls. SPM results superimposed on glass brain (a) and standard T1 MRI template images (b e) show significant GMV reductions in bilateral insula, motor/premotor, prefrontal, cingulate cortex, right posterior parietal cortex, and orbitofrontal cortex (thresholded at P<0.001, uncorrected for multiple comparisons at a voxel level; corrected P<0.05 after small volume corrections). The colour bar represents the T-values. The left side of each picture is the left side of the brain. Reprinted with permission from the Blackwell Publishing. 77 발작을발생시킨다는직접적인증거는없다. 평소두통이없던환자에서만성통증조절을위해 periaqueductal grey (PAG) 에주입된전극을자극했을때편두통과비슷한두통이유발되었다는 1987 년 Raskin 등의논문이편두통의뇌줄기가설을임상적으로증명해주는유일한증례보고이다. 60 뇌줄기의혈관종 61 또는혈관기형이 62 편두통을발생시켰다는보고들도있어신체통증조절의역할을한다고알려진 PAG 가편두통의발병기전에도역할을할것이라는가설도제시되었다. 63 더구나뇌줄기 ( 교뇌 ) 안에서도 activation 되는위치가논문마다조금씩다르게보고되었는데 36,52,55,57,58 이는 PET, BOLD MRI 영상의해상력과영상통계처리방법에한계가있기때문이라고생각한다. 그러므로뇌줄기의어떤특정한핵이편두통의두통발생과통증전달과정에관여하는지에관해서는논란이있고추후더연구해야할부분이다. 4. 형태학적변화 (morphometric changes) 편두통, 군발두통을포함하는일차두통증후군은뇌의구조적이상없이주기적뇌기능이상으로부터두통이발생된다는견해는현재모두가인정하고있다. 1,56 그러나 편두통에서겉질밑백색질에 MRI 에서고신호를보이는다발성병터가관찰될수있다는여러연구들이발표되었다 이병터의의미는불명확하나반복적인두통발작에동반되는국소적인뇌관류저하에따른변화일수있으며편두통이허혈뇌졸중의위험인자로작용할수있다는것을의미한다 년에네덜란드의 20~60 세의지역인구를기반으로한 CAMERA 연구 (Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis study) 는대단위전향적단면조사 MRI 연구이고고혈압, 당뇨병. 흡연등의뇌졸중을유발하는위험인자를고려했다는점에서주목을받는다. 67,68 조짐또는무조짐편두통환자군의천막위백색질병터는대조군과의미있는차이가없었고특히조짐편두통환자군에서천막밑소뇌에작은크기의뇌경색과비슷한병터들 (infarct-like lesions) 이많이관찰되었다. 저자들은이병터는뇌경색을유발하는흔한원인인죽상경화증이나소혈관질환보다는반복되는편두통발작에따른뇌관류저하또는색전에의해발생했을가능성을제시하였다. 67,68 위에서언급한 PET 와 BOLD MRI 연구에서비교적일관적으로뇌줄기와중추성통증전달을담당하는부위들의 20 Korean J Clin Neurophysiol / Volume 10 / June, 2008

9 편두통의기능적뇌영상 activation 이관찰되었는데, 최근에연구자들은이러한뇌의국소적인기능변화가구조적인변화를일으킬가능성을검증하기시작하였다. 특히군발두통에서는두통과같은쪽의아래쪽시상하부의 activation과함께 voxelbased morphometry (VBM) 를이용하여같은시상하부회색질의구조적인변화가관찰되었다. 69 이결과는서로다른두가지의영상기법으로기능적그리고형태학적변화를관찰한것으로시상하부가군발두통의특이영역이라는가능성과함께시상하부가군발두통의병태생리에서중요한역할을하는것을강력히의미한다. VBM 은고해상도의 3차원 T1 강조영상을이용하는완전자동화되고객관적인 MRI 분석방법으로환자군과대조군사이에국소적인회색질또는백색질의농도 (density, concentration) 와부피 (volume) 의눈으로는알기어려운미세한차이를알아보는데매우유용하여근래에많이사용하고있다. 70, 년에처음발표된편두통의 VBM 연구에의하면조짐편두통 11명과무조짐두통 17명은대조군과뇌의구조적인차이를보이지않았다. 72 만성편두통으로인한약물유발두통 (medication-overuse headache) 환자 20 명의 VBM 연구에서도대조군과유의한차이를보이지않았다. 73 상기두연구에의거하여편두통은군발두통과는달리오로지뇌의기능적변화에의해서만두통이발생하고구조적인변화는동반하지않는것으로간주하였다. 7 그러나 Rocca 등은 4개이상의백색질병터가있는편두통환자들의 3 Tesla MRI VBM 분석에서통증전달에관여하는구조물인 insula, anterior cingulate gyrus, prefrontal cortex, temporal cortex 등의회색질농도가정상인보다감소되어있으며이감소된정도는편두통의이환기간과백색질병터의개수와음의상관관계가있음을보고하였다. 74 또한편두통특이영역으로생각하는 dorsolateral pons 와 preaqueductal grey 의회색질농도가의미있게증가되어있었으며편두통환자의뇌에구조적또는형태학적인변화가있을가능성을처음으로제시했다. 74 최근에같은 VBM 방법으로비슷한결과가도출되었다 최근의다른논문에서도편두통환자 35명에서 anterior/posterior cingulate cortex, right insula cortex의회색질부피가감소되어있었다. 75 김등의 VBM 연구에서도백색질병터가없는 20명의삽화성편두통 (episodic migraine) 환자들은통증전달에관여하는부위의회색질부피가대조군보다감소되어있었으며그감소정도는편두통의이환기간과두통발작의빈도와음의상관관계를보였다 (Fig. 4). 77 즉, 반복적인편두통발작으로통증전달에관여하는뇌의구조물이손상을입어결국부 피가감소됨을의미한다. 그러나편두통발생의특이영역인뇌줄기부위에는의미있는부피변화가관찰되지않았고비슷한소견이만성요통환자 78,79 또는환지통 (phantom limb pain) 환자의 80 VBM 연구에서도관찰되어, 이러한형태학적인변화는편두통의특이적인변화가아니며다른종류의통증을유발하는질환에서도관찰될수있는변화라고할수있다. 77 또한편두통환자들의몸감각겉질의두께가증가되어있다는보고도있다. 81 비슷한 MRI 분석방법에도위에서열거한연구들마다상이한결과를보이는이유는아마도편두통이유전적으로매우이질적인질환이기때문이라고생각한다. 그러므로편두통환자의뇌에구조적인변화가있다는점을일반화하기위해서는유전적으로동일한환자군을선택해야하며환자- 대조군사이의단면연구보다는일정기간을두고두번이상검사하여분석하는추적연구를해야한다. 결 론 기능적뇌영상은편두통의해부학적기능과병태생리를이해하는데매우중요한역할을했다고할수있다. 과거에편두통은단순히혈관의확장에서비롯된다는혈관성두통의개념이지배적이었으나근래에 PET, SPECT, BOLD MRI, VBM 과같은새로운뇌영상기법을이용한연구들의기여로편두통에서혈관성변화가두통발작을유발하는일차적인원인으로작용하지않는다는점이밝혀지게되었다. PET 연구로편두통발작의생성에뇌줄기 ( 특히교뇌와중간뇌 ) 의기능이상이결정적역할을한다는사실이밝혀졌고 SPECT 와 BOLD MRI 연구로조짐편두통에서시각조짐의발생가설로제시되었던후두엽겉질의전기생리적인변화인겉질확산성억제가입증되었다. 또한 VBM 연구로편두통환자의뇌가두통발작이반복될수록구조적인변화를동반한다는가능성도알려지게되었다. 이러한기능적뇌영상기법은과학의발전과더불어계속진화하고있으며이들을이용한연구에힘입어편두통과삼차신경혈관계와의연관성및두통발생기전에대한폭넓은이해가제공되고획기적인편두통예방과치료방법이개발되기를기대한다. REFERENCES 1. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1: Goadsby PJ, Lipton RB, Ferrari MD. Migraine--current understanding and treatment. N Engl J Med 2002;346: Korean J Clin Neurophysiol / Volume 10 / June,

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