untitled

Transcription

1 Brain & N eurorehabilitation Vol. 1, No. 1, March, 2008 신경조절과뇌가소성 서울대학교의과대학재활의학교실, 분당서울대학교병원재활의학과 백남종 Neuromodulation and Brain Plasticity Nam-Jong Paik, M.D., Ph.D. Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital Recently neuromodulation therapies such as peripheral nerve stimulation, non-invasive cortical stimulation that could potentially regulate the excitability of the brain are being actively applied to enhance neural recovery in the neurorehabilitation with promising results. Brain plasticity refers the property of the central nervous system to reorganize and remodel following new environmental requirements or injury. In this review, cortical plastic changes after neuromodulation therapies will be described. (Brain & NeuroRehabilitation 2008; 1: 12-19) Key Words: neuromodulation, plasticity, transcranial magnetic stimulation, transcranial DC stimulation, stroke 신경가소성이란중추신경계의손상후뇌가재구성 (reorganize) 혹은재배치 (remodel) 하는능력을일컫는것으로주위환경이나병변에맞도록대뇌피질의기능과형태가변하는신경계의적응 (neural adaption) 과정이라할수있다. 1-4 뇌의가소성은뇌병변이후학습및기억등대뇌기능의회복에중요한역할을한다. 5 가소적변화는주로대뇌에광범위하게분포하고있는시냅스에서일어나며, 이를통해뇌안의네트워크가새로이구성되게된다. 6 재활치료의측면에서는이러한뇌가소성으로인하여궁극적으로행동학적변화, 즉기능회복이일어나는것이바람직하지만뇌가소성의변화는기능회복에적응적 (adaptive) 일수도, 비적응적 (maladaptive) 일수도, 혹은기능회복과아무런상관이없을수도있다. 또한뇌가소성은연습 (practice) 과치료 (intervention) 에의해촉진될수있으므로재활치료의주된요점은뇌가소성이바람직한방향으로일어나도록하는것이다. 최근뇌의기능을조절하는방법으로유전자치료, 줄기세포치료등이연구되고있지만아직실용화되기에는많은시간을기다려야하며, 약물요법을적용하기도하지만 교신저자 : 백남종, 경기도성남시분당구구미로 , 분당서울대학교병원재활의학과 Tel: , Fax: njpaik@snu.ac.kr 약물은뇌의활성을원하는방향으로조절하는데제한이있어신경조절 (neuromodulation) 이뇌가소성을증진시키는재활치료의보조수단으로주목을받고있다. 7 신경조절은공간적, 시간적특이성이있고, 흥분성혹은억제성자극을조절하여가할수있으므로경쟁적인부위는억제시키고뇌의특정부위를항진시킬수있으며, 약물과상호작용이있고, 무엇보다도후-효과 (after-effect) 를이용하여행동학적회복과뇌가소성의변화를일으킬수있다 본종설에서는최근에운동, 감각, 인지영역등에서임상적적용이확대되고있는신경조절치료법중비침습적뇌자극을중심으로알아보고자한다. 연습 (practice) 과훈련 (training) 뇌는수동적이지도또한중립적이지도않다. 따라서가소성이일어나려면집중 (attention) 을통한연습이반복되어야하며, 이를사용자의존성가소성 (use-dependent plasticity, UDP) 이라고한다. 경두개자기자극으로근육이수축 (twich) 하는방향의반대방향으로지속적으로연습을시킨후, 다시경두개자기자극을가하면이전의근육이수축하는방향과는반대방향인연습한방향으로근육이수축하는것을관찰할수있는데이는사용자의존성가소성을보여주는한예라할수있겠다 물론신경학적회복자체로도가소성이일어나지만운동습득과회복모두연습이반복되어야가소성이효과적 12

2 백남종 : 신경조절과뇌가소성 으로일어나게된다. 24,25 또한최근에는뇌손상후회복과운동습득의가소성변화가비슷한기전으로일어나는것이알려지면서이에대한중요성이더욱강조되게되었다. 5,23,26-29 따라서아래에소개되는신경조절치료도단순한적용으로서는효과를기대하기어려우며사용자의집중을통한연습이전제되어야한다. 최근에적용이늘고있는구속치료법 30,31 이나체중부하지지보행치료법, 32,33 신경근육자극치료법, 로보트를이용한치료법, 37,38 가상현실을이용한치료법 39 등은모두이러한사용자의존성가소성을극대화하기위한시도라고이해되어야한다. 이러한사용자의존성가소성은아드레날린혹은콜린계통의기전을통하여강화되며이는약물보조치료의이론적근거가될수있다. 40 그외에자신이나남의동작을관찰하거나 (action observation) 움직임을상상 (mental imagery) 함으로도운동기능의회복을촉진할수있는데, 이는전운동영역 (premotor cortex) 과하두정엽 (infra-parietal lobe) 에있는것으로알려진거울뉴런 (mirror neuron) 의역할이라고생각되고있다 즉동작을관찰하거나움직임을상상할때활성화되는뇌의영역이운동습득 (motor learning) 때활성화되는뇌의영역과많이겹치는것이알려지면서이러한치료법도운동기능의회복을촉진할가능성이제시되었는바, 특히발병초기에환자의근력이없어다른방법의적용이불가능할때유용할것으로여겨진다. 48,49 체성감각자극 (somatosensory stimulation) 체성감각자극은운동기능및운동의습득, 섬세운동및운동기능의재배치에영향을미친다. 이는감각피질과운동피질이해부학적, 기능적으로밀접한관계에있기때문인데, 50 말초감각신경의장애가있을때운동기능이저하되는것으로도쉽게알수있다. 51 체성감각자극으로피질의흥분도를조절할수있는데, 90 Hz 이상의고빈도자극에서는대뇌피질의흥분도를억제하고 10 Hz 이하의저빈도자극에서는대뇌피질의흥분도를항진시킨다 체성감각자극은자극을준부위의감각신경과연관된운동신경영역의흥분도만을변화시키는위치적인특이도 (topographical specificity) 가있으며보통약한근육수축을유발하는강도의자극으로 2시간정도자극을가하면 2시간이내의후-효과를나타낸다. 그기전으로는경두개자기자극 (transcranial magnetic stimulation, TMS) 으로측정한피질내억제 (intracortical inhibition, ICI) 가감소 되는것으로미루어 GABA가매개하는대뇌피질의탈억제 (disinhibition) 가언급되고있다. 약물작용으로는 GABA 수용체의 agonist인 lorazepam 에의해체성감각자극의후-효과가차단되지만 NMDA 수용체의길항체인 dextromethorphan에의하여는영향을받지않는다 체성감각자극은주로운동신경의기능을향상시키기위해적용하는데, 뇌졸중환자에서수부에체성감각자극후파악력이증가되고일상생활동작과연관이있는 Jebsen-Taylor 수부기능검사의수행시간이단축되는것이알려져있으며, 55,62,63 인두부에자극하였을때는연하기능이향상된다는것이보고된바있다. 64 연구를위해가짜자극 (sham stimulation) 이필요할때에는전극만붙이고자극을가하지않거나, 위치적으로관련이없는부위를자극하거나혹은대뇌피질에영향을미치지않는빈도로자극하는방법을고려할수있다. 57 경막외자극 (epidural stimulation) 및뇌심부자극 (deep brain stimulation) 경막외자극은경막외공간에침습적으로수술을통해전극을심어전기자극을가하는것으로만성뇌졸중환자에서운동기능을향상시키는것이적은환자를대상으로한연구에서일부보고되었다. 65 Brown 등 65 은자극의위치를기능적자기공명영상 (functional magnetic resonance imaging, fmri) 으로정한후, 250 ms 지속시간의 50 Hz 전기자극을 3초간움직임이일어나는세기혹은 15 ma로자극하는변수를이용하였다. 보다큰규모의환자를대상으로이에대한지속적인임상시험이현재진행중이므로그효과는조금더기다려봐야한다. 뇌심부자극은주로파킨슨씨병에임상적으로적용이확대되고있으나, 아직신경재활영역에서의적용은없다. 현재사경등의운동장애와우울증, 강박장애, Tourette 증후군, 정신분열증등의신경정신과적영역, 통증, 간질, 심지어고혈압, 섭식장애등에도그적용이확대되고있으므로곧신경재활영역에서도그적용이이루어지기를기대한다. 15,66 반복적경두개자기자극 (repetitive transcranial magnetic stimulation, rtms) 반복적경두개자기자극은빈도수에따라뇌피질의흥분도를조절한다. 1 Hz 이하의저빈도에서는흥분도를억제하고 5 Hz 이상의고빈도에서는흥분도를항진시킨다. 지속시간은대개 30분이내로생각되며, 작용기전은운동 13

3 Brain& NeuroRehabilitation:2008; 1: 12~19 습득에중요한 long-term potentiation (LTP) 과 long-term depression (LTD) 에의한것으로알려져있다. 8,67-72 반복적경두개자기자극을가하게되면자극을가한부위뇌피질의흥분도만을변화시키는것이아니라, 이와연관된네트워크전체에걸쳐영향을미치게된다. 73 최근에는반복적경두개자기자극의자극빈도를변형한 theta burst 자극 (theta burst stimulation, TBS) 이활발히연구되고있다. Theta burst 자극은통상적인반복적경두개자기자극에비해짧은시간의자극으로도보다길고강력한효과를얻는다고한다. 뇌피질흥분도의효과는지속적 theta burst 자극은억제성, 간헐적 theta burst 자극은흥분성효과를나타내며, 그기전은경두개자기자극과동일하다고생각된다. 74 연구를위해가짜자극이필요할때에는자극코일을수직으로하여자극이대뇌피질에영향을미치지않도록하거나, 75 가짜자극을위해고안된코일을사용할수있다. 76 경두개직류자극 (transcranial direct current stimulation, tdcs) 경두개직류자극은극성에따라뇌피질의흥분도를조절한다. 음극자극 (cathodal stimulation) 은신경세포의막전위를과분극 (hyperpolarization) 시킴으로써흥분도를억제하고, 양극자극 (anodal stimulation) 은막전위를탈분극 (depolarization) 시킴으로써흥분도를항진시킨다. 그러나경두개직류자극은반복적경두개자기자극과는달리휴식기의신경을자발적으로발사 (firing) 시키지는못하므로경두개직류극화 (transcranical direct current polarization) 라고하기도한다. 보통 1 2 ma의세기로 10 20분정도자극하며, 이경우후-효과는 90분정도지속된다고알려져있다 작용기전은 NMDA 수용체의활성화에의한기전과세포막에작용하는기전이동시에작용한다고알려져있다. 이는나트륨통로차단제인 carbamazepine이나칼슘통로차단제인 flunarizine, 그리고 NMDA 수용체길항제인 dextromethorphan에의해후-효과가차단되는것으로알수있다. 81,82,86-88 경두개직류자극역시반복적경두개자기자극과마찬가지로자극을가한부위보다넓은네트워크에걸쳐흥분도의변화를일으킨다 경두개직류자극은경두개자기자극에비해, 장비가가격면에서저렴하고적용하기가쉬우며물리치료, 작업치료등운동습득이진행되는동안에동시에적용할수있는장점이있어, 신경재활영역에서의적용확대가기대된 다. 또한연구적인측면에서는자극시감각이미약하고불편감이적어눈가림적용이용이한장점이있다. 89 눈가림적용을위하여가짜자극을가하는경우는일정시간 (30 초 ~1분 ) 이지난후자극을멈춘다. 이경우에도피험자는진짜와가짜여부를잘구별하지못한다. 89 짝지은연관자극 (paired associative stimulation, PAS) 짝지은연관자극은말초의전기자극이대뇌피질에도달할무렵경두개자기자극을가함으로써뇌피질의흥분도를조절하는자극법으로말초전기자극과경두개자기자극간의시간간격 (interstimulus interval) 에의해흥분도가좌우된다. 상지자극의경우자극간시간간격이 25 ms 정도이면흥분이항진되지만이보다짧은 10 ms 정도의자극간시간간격에서는흥분도가억제된다. 90 일반적으로 0.05 Hz의빈도로 90쌍의자극을가했을경우 60분정도의가소성변화가지속된다고알려져있다. 또한대상자가주의 (attention) 를기울여야가소성변화가나타나며가소성은체성감각자극과마찬가지로자극을준부위의흥분도만변하는특이도 (topographical specificity) 가있다. 작용기전은역시운동습득에중요한 long-term potentiation 와 long-term depression에의한것으로알려져있다. 91 뇌졸중환자에서하지에짝지은연관자극을적용하고보행기능이향상되었다는보고가있다. 92 최근에는 theta burst 자극과비슷한개념으로 5 Hz의운동역치이하의말초신경의전기자극과 5 Hz의반복적경두개자기자극을짝지음으로써지속기간을연장하였다는보고가있다. 이를반복적짝지은연관자극 (repetitive paired associative stimulation, rpas) 이라고하는데 2분의자극으로 6시간이상의지속적인뇌가소성변화효과를얻을수있다고한다. 93 신경조절기법에의한뇌가소성의변화 최근의연구에의하면정상적인대뇌는뇌량 (corpus callosum) 을통한경로 (transcallosal fiber) 를통해양측대뇌가서로억제를하고있어균형을이루고있는데, 뇌졸중등한쪽대뇌에병변이발생하면이환측에서건측으로가하는억제가약해져건측에서이환측으로가하는억제가상대적으로증가하는것이관찰되었다. 29, 따라서이론적으로는대뇌자극을통하여이환측대뇌의활성도를증가시키거나, 혹은건측의대뇌의활성도를감소시켜건측에서이환측으로가하는억제를감소시킴으로써기 14

4 백남종 : 신경조절과뇌가소성 능의회복을증가시킬수있다. 11,96,101 이러한이론을바탕으로최근에는반복적경두개자기자극이나경두개직류자극과같은비침습적대뇌자극을통하여이러한양측대뇌의균형상태를복원함으로써운동기능의회복을촉진시키려는시도가이루어지고있다 ( 이환측대뇌자극 : 경막외자극, 65 반복적경두개자기자극, 102,103 경두개직류자극 101,104,105 ; 건측대뇌자극 : 반복적경두개자기자극, 106,107 경두개직류자극 105 ). 대부분의연구보고에의하면만성뇌졸중환자에게이러한신경조절기법을적용하였을경우 5 10% 의운동기능이향상되었다고한다. 최근에는이러한제한점을극복하기위하여지속적인자극이누적효과혹은보다오랜지속효과가있는가에관심을기울이고있다. 108 이러한개념은실어증이나편측무시의회복을위한신경조절에도적용되는데, 특히직간접적인신경손상에의하여오히려기능이증진되는것을역설적기능항진 (paradoxical functional facilitation) 109 이라하고, 실어증 110 이나편측무시의병변을유발한반대측대뇌의대응부위를신경조절기법으로가상병변 (virtual lesion) 을유발시킴으로써이환측의기능이향상되었다는것이보고되고있다 한편, 중추신경계는네트워크의활성도를일정하게유지하려는성질이있어신경네트워크의활동이많아져활성도가증가되면시냅스는억제되려는방향으로작용하고 (long-term depression), 반대로네트워크의활성도가감소하면시냅스의기능은항진 (long-term potentiation) 되는경향을보인다. 이를뇌의항상적가소성 (homeostatic plasticity) 이라고한다. 114,115 이를이용하여전체적인시냅스의강도는일정수준에서유지하면서선택적으로시냅스의활성방향을선택적으로원하는방향으로유도할수있는데, 예를들어운동연습 (motor practice) 등으로뇌의활성도가증진된전-조건 (preconditioning) 상태에서는이후의항진성신경조절이오히려억제성효과를나타내고, 억제성신경조절은전-조절이없는상태보다더욱억제되는효과를유발한다. 116 신경조절치료에서는미리전-조건조작을가하여인위적으로신경조절에대한대뇌의반응을증폭하여항진하거나억제시키는데응용할수있다 결론적으로최근의신경조절기법은재활훈련의효과를증대시키기위한보조적수단으로그적용이확대되고있으며, 특히운동기능영역과인지기능의회복 12, 을촉진하기위하여많이적용되고있다. 운동기능영역의회복을위하여운동기능이전혀없을때에는운동상상기법 (mental imagery) 이나운동관찰 (action observation) 을시행하고, 운동기능이불완전할때에는반복적인연습으로 Table 1. Intervention strategies for Improvement of Motor Function in Neurorehabilitation Mental imagery & Action observation Passive and assisted motion Manual, Robots Motor training Electrical stimulation NMES (EMG triggered > passive) Nerve (pure sensory, mixed) vs. Muscle Low vs. High frequency Below vs. Above motor threshold Cortical stimulation Brain polarization (tdcs, anodal vs. cathodal) rtms (Low vs. high frequency) Theta Burst Stimulations Epidural stimulation (invasive) Paired associative stimulation Pharmacotherapy 운동습득을진행하고, 이과정에서보조적으로각종말초혹은대뇌피질자극, 혹은약물요법을병행함으로써운동기능을보다빠르게, 보다많이회복할수있을것이라고기대한다 (Table 1). 참고문헌 1) Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience. 2002;111: ) Cohen LG, Ziemann U, Chen R. Mechanisms, functional relevance and modulation of plasticity in the human central nervous system. Electroencephalogr Clin Neurophysiol Suppl. 1999;51: ) Cohen LG, Brasil-Neto JP, Pascual-Leone A, Hallett M. Plasticity of cortical motor output organization following deafferentation, cerebral lesions, and skill acquisition. Adv Neurol. 1993;63: ) Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci. 2005;28: ) Krakauer JW. Motor learning: Its relevance to stroke recovery and neurorehabilitation. Curr Opin Neurol. 2006;19: ) Cooke SF, Bliss TV. Plasticity in the human central nervous system. Brain. 2006;129: ) Walsh V, Desmond JE, Pascual-Leone A. Manipulating brains. Behav Neurol. 2006;17: ) Fregni F, Pascual-Leone A. Technology insight: Noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rtms and tdcs. Nat Clin Pract Neurol. 2007;3: ) Alonso-Alonso M, Fregni F, Pascual-Leone A. Brain stimulation in poststroke rehabilitation. Cerebrovasc Dis. 2007; 15

5 Brain& NeuroRehabilitation:2008; 1: 12~19 24 Suppl 1: ) Pascual-Leone A. Disrupting the brain to guide plasticity and improve behavior. Prog Brain Res. 2006;157: ) Harris-Love ML, Cohen LG. Noninvasive cortical stimulation in neurorehabilitation: A review. Arch Phys Med Rehabil. 2006;87:S ) Floel A, Cohen LG. Contribution of noninvasive cortical stimulation to the study of memory functions. Brain Res Rev. 2007;53: ) Floel A, Cohen LG. Translational studies in neurorehabilitation: From bench to bedside. Cogn Behav Neurol. 2006; 19: ) Hummel FC, Cohen LG. Drivers of brain plasticity. Curr Opin Neurol. 2005;18: ) George MS. Stimulating the brain. Sci Am. 2003;289: ) Lefaucheur JP. Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rtms). Neurophysiol Clin. 2006;36: ) Hummel FC, Cohen LG. Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? Lancet Neurol. 2006;5: ) Talelli P, Rothwell J. Does brain stimulation after stroke have a future? Curr Opin Neurol. 2006;19: ) Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol. 2001;112: ) Butefisch CM, Khurana V, Kopylev L, Cohen LG. Enhancing encoding of a motor memory in the primary motor cortex by cortical stimulation. J Neurophysiol. 2004;91: ) Classen J, Liepert J, Wise SP, Hallett M, Cohen LG. Rapid plasticity of human cortical movement representation induced by practice. J Neurophysiol. 1998;79: ) Lotze M, Cohen LG. Volition and imagery in neurorehabilitation. Cogn Behav Neurol. 2006;19: ) Kelly C, Foxe JJ, Garavan H. Patterns of normal human brain plasticity after practice and their implications for neurorehabilitation. Arch Phys Med Rehabil. 2006;87:S ) Platz T, van Kaick S, Moller L, Freund S, Winter T, Kim IH. Impairment-oriented training and adaptive motor cortex reorganisation after stroke: A ftms study. J Neurol. 2005;252: ) Nudo RJ, Plautz EJ, Frost SB. Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve. 2001;24: ) Ward NS. The neural substrates of motor recovery after focal damage to the central nervous system. Arch Phys Med Rehabil. 2006;87:S ) Butefisch CM, Kleiser R, Seitz RJ. Post-lesional cerebral reorganisation: Evidence from functional neuroimaging and transcranial magnetic stimulation. J Physiol Paris. 2006;99: ) Koski L, Mernar TJ, Dobkin BH. Immediate and long-term changes in corticomotor output in response to rehabilitation: Correlation with functional improvements in chronic stroke. Neurorehabil Neural Repair. 2004;18: ) Butefisch CM. Plasticity in the human cerebral cortex: Lessons from the normal brain and from stroke. Neuroscientist. 2004;10: ) Wolf SL, Winstein CJ, Miller JP, Taub E, Uswatte G, Morris D, Giuliani C, Light KE, Nichols-Larsen D. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: The excite randomized clinical trial. JAMA. 2006;296: ) Taub E, Uswatte G, King DK, Morris D, Crago JE, Chatterjee A. A placebo-controlled trial of constraint-induced movement therapy for upper extremity after stroke. Stroke. 2006;37: ) Husemann B, Muller F, Krewer C, Heller S, Koenig E. Effects of locomotion training with assistance of a robot-driven gait orthosis in hemiparetic patients after stroke: A randomized controlled pilot study. Stroke. 2007;38: ) Moseley AM, Stark A, Cameron ID, Pollock A. Treadmill training and body weight support for walking after stroke. Stroke. 2003;34: ) Cauraugh J, Light K, Kim S, Thigpen M, Behrman A. Chronic motor dysfunction after stroke: Recovering wrist and finger extension by electromyography-triggered neuromuscular stimulation. Stroke. 2000;31: ) Church C, Price C, Pandyan AD, Huntley S, Curless R, Rodgers H. Randomized controlled trial to evaluate the effect of surface neuromuscular electrical stimulation to the shoulder after acute stroke. Stroke. 2006;37: ) Daly JJ, Roenigk K, Holcomb J, Rogers JM, Butler K, Gansen J, McCabe J, Fredrickson E, Marsolais EB, Ruff RL. A randomized controlled trial of functional neuromuscular stimulation in chronic stroke subjects. Stroke. 2006;37: ) Hesse S, Werner C, Pohl M, Rueckriem S, Mehrholz J, Lingnau ML. Computerized arm training improves the motor control of the severely affected arm after stroke: a singleblinded randomized trial in two centers. Stroke. 2005;36: ) O'Malley MK, Ro T, Levin HS. Assessing and inducing neuroplasticity with transcranial magnetic stimulation and robotics for motor function. Arch Phys Med Rehabil. 2006; 87:S ) You SH, Jang SH, Kim YH, Hallett M, Ahn SH, Kwon YH, Kim JH, Lee MY. Virtual reality-induced cortical reorganization and associated locomotor recovery in chronic stroke: An experimenter-blind randomized study. Stroke. 2005;36: ) Floel A, Breitenstein C, Hummel F, Celnik P, Gingert C, Sawaki L, Knecht S, Cohen LG. Dopaminergic influences on formation of a motor memory. Ann Neurol. 2005;58: ) Braun SM, Beurskens AJ, Borm PJ, Schack T, Wade DT. The effects of mental practice in stroke rehabilitation: A systematic review. Arch Phys Med Rehabil. 2006;87: ) Buccino G, Solodkin A, Small SL. Functions of the mirror neuron system: Implications for neurorehabilitation. Cogn Behav Neurol. 2006;19:

6 백남종 : 신경조절과뇌가소성 43) Mattar AA, Gribble PL. Motor learning by observing. Neuron. 2005;46: ) Stefan K, Classen J, Celnik P, Cohen LG. Concurrent action observation modulates practice-induced motor memory formation. Eur J Neurosci. 2008;27: ) Stefan K, Cohen LG, Duque J, Mazzocchio R, Celnik P, Sawaki L, Ungerleider L, Classen J. Formation of a motor memory by action observation. J Neurosci. 2005;25: ) Liu KP, Chan CC, Lee TM, Hui-Chan CW. Mental imagery for promoting relearning for people after stroke: a randomized controlled trial. Arch Phys Med Rehabil. 2004;85: ) Butler AJ, Page SJ. Mental practice with motor imagery: Evidence for motor recovery and cortical reorganization after stroke. Arch Phys Med Rehabil. 2006;87:S ) Sharma N, Pomeroy VM, Baron JC. Motor imagery: a backdoor to the motor system after stroke? Stroke. 2006; 37: ) Pomeroy VM, Clark CA, Miller JS, Baron JC, Markus HS, Tallis RC. The potential for utilizing the "Mirror neurone system" To enhance recovery of the severely affected upper limb early after stroke: a review and hypothesis. Neurorehabil Neural Repair. 2005;19: ) Pavlides C, Miyashita E, Asanuma H. Projection from the sensory to the motor cortex is important in learning motor skills in the monkey. J Neurophysiol. 1993;70: ) Rothwell JC, Traub MM, Day BL, Obeso JA, Thomas PK, Marsden CD. Manual motor performance in a deafferented man. Brain. 1982;105(Pt 3): ) Ellrich J, Schorr A. Low-frequency stimulation of trigeminal afferents induces long-term depression of human sensory processing. Brain Res. 2004;996: ) Charlton CS, Ridding MC, Thompson PD, Miles TS. Prolonged peripheral nerve stimulation induces persistent changes in excitability of human motor cortex. J Neurol Sci. 2003;208: ) Kimberley TJ, Lewis SM, Auerbach EJ, Dorsey LL, Lojovich JM, Carey JR. Electrical stimulation driving functional improvements and cortical changes in subjects with stroke. Exp Brain Res. 2004;154: ) Wu CW, Seo HJ, Cohen LG. Influence of electric somatosensory stimulation on paretic-hand function in chronic stroke. Arch Phys Med Rehabil. 2006;87: ) Ridding MC, McKay DR, Thompson PD, Miles TS. Changes in corticomotor representations induced by prolonged peripheral nerve stimulation in humans. Clin Neurophysiol. 2001;112: ) Kaelin-Lang A, Luft AR, Sawaki L, Burstein AH, Sohn YH, Cohen LG. Modulation of human corticomotor excitability by somatosensory input. J Physiol. 2002;540: ) Chen R, Corwell B, Hallett M. Modulation of motor cortex excitability by median nerve and digit stimulation. Exp Brain Res. 1999;129: ) Kobayashi M, Ng J, Theoret H, Pascual-Leone A. Modulation of intracortical neuronal circuits in human hand motor area by digit stimulation. Exp Brain Res. 2003;149:1-8 60) Sailer A, Molnar GF, Cunic DI, Chen R. Effects of peripheral sensory input on cortical inhibition in humans. J Physiol. 2002;544: ) Ridding MC, Brouwer B, Miles TS, Pitcher JB, Thompson PD. Changes in muscle responses to stimulation of the motor cortex induced by peripheral nerve stimulation in human subjects. Exp Brain Res. 2000;131: ) Conforto AB, Kaelin-Lang A, Cohen LG. Increase in hand muscle strength of stroke patients after somatosensory stimulation. Ann Neurol. 2002;51: ) Celnik P, Hummel F, Harris-Love M, Wolk R, Cohen LG. Somatosensory stimulation enhances the effects of training functional hand tasks in patients with chronic stroke. Arch Phys Med Rehabil. 2007;88: ) Fraser C, Power M, Hamdy S, Rothwell J, Hobday D, Hollander I, Tyrell P, Hobson A, Williams S, Thompson D. Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury. Neuron. 2002;34: ) Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: A prospective, multicenter safety study. Neurosurgery. 2006;58: ) Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, Fritz B, Eisenberg B, O'Connor J, Kobylarz EJ, Farris S, Machado A, McCagg C, Plum F, Fins JJ, Rezai AR. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007;448: ) Di Lazzaro V, Dileone M, Profice P, Pilato F, Cioni B, Meglio M, Capone F, Tonali PA, Rothwell JC. Direct demonstration that repetitive transcranial magnetic stimulation can enhance corticospinal excitability in stroke. Stroke. 2006;37: ) Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2: ) George MS, Nahas Z, Kozel FA, Li X, Denslow S, Yamanaka K, Mishory A, Foust MJ, Bohning DE. Mechanisms and state of the art of transcranial magnetic stimulation. J Ect. 2002;18: ) George MS. New methods of minimally invasive brain modulation as therapies in psychiatry: Tms, mst, vns and dbs. Zhonghua Yi Xue Za Zhi (Taipei). 2002;65: ) Fitzgerald PB, Brown TL, Daskalakis ZJ. The application of transcranial magnetic stimulation in psychiatry and neurosciences research. Acta Psychiatr Scand. 2002;105: ) Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol. 2001;112: ) Siebner HR, Peller M, Willoch F, Minoshima S, Boecker H, Auer C, Drzezga A, Conrad B, Bartenstein P. Lasting cortical activation after repetitive tms of the motor cortex: a glucose metabolic study. Neurology. 2000;54: ) Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. 17

7 Brain& NeuroRehabilitation:2008; 1: 12~19 Theta burst stimulation of the human motor cortex. Neuron. 2005;45: ) Lisanby SH, Gutman D, Luber B, Schroeder C, Sackeim HA. Sham tms: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry. 2001;49: ) Rossi S, Ferro M, Cincotta M, Ulivelli M, Bartalini S, Miniussi C, Giovannelli F, Passero S. A real electro-magnetic placebo (remp) device for sham transcranial magnetic stimulation (tms). Clin Neurophysiol. 2007;118: ) Purpura DP, McMurtry JG. Intracellular activities and evoked potential changes during polarization of motor cortex. J Neurophysiol. 1965;28: ) Priori A. Brain polarization in humans: a reappraisal of an old tool for prolonged non-invasive modulation of brain excitability. Clin Neurophysiol. 2003;114: ) Wassermann EM, Grafman J. Recharging cognition with dc brain polarization. Trends Cogn Sci. 2005;9: ) Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, Frackowiak RS. How does transcranial dc stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci. 2005;22: ) Nitsche MA, Liebetanz D, Schlitterlau A, Henschke U, Fricke K, Frommann K, Lang N, Henning S, Paulus W, Tergau F. Gabaergic modulation of dc stimulation-induced motor cortex excitability shifts in humans. Eur J Neurosci. 2004; 19: ) Nitsche MA, Nitsche MS, Klein CC, Tergau F, Rothwell JC, Paulus W. Level of action of cathodal dc polarisation induced inhibition of the human motor cortex. Clin Neurophysiol. 2003;114: ) Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial dc motor cortex stimulation in humans. Neurology. 2001;57: ) Lang N, Nitsche MA, Paulus W, Rothwell JC, Lemon RN. Effects of transcranial direct current stimulation over the human motor cortex on corticospinal and transcallosal excitability. Exp Brain Res. 2004;156: ) Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS, Fricke K, Liebetanz D, Lang N, Antal A, Paulus W, Tergau F. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol. 2005;568: ) Liebetanz D, Nitsche MA, Tergau F, Paulus W. Pharmacological approach to the mechanisms of transcranial dcstimulation-induced after-effects of human motor cortex excitability. Brain. 2002;125: ) Liebetanz D, Fregni F, Monte-Silva KK, Oliveira MB, Amancio-dos-Santos A, Nitsche MA, Guedes RC. Aftereffects of transcranial direct current stimulation (tdcs) on cortical spreading depression. Neurosci Lett. 2006;398: ) Nitsche MA, Lampe C, Antal A, Liebetanz D, Lang N, Tergau F, Paulus W. Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex. Eur J Neurosci. 2006;23: ) Gandiga PC, Hummel FC, Cohen LG. Transcranial dc stimulation (tdcs): A tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol. 2006;117: ) Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain. 2000;123 Pt 3: ) Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J. Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol. 2002;543: ) Uy J, Ridding MC, Hillier S, Thompson PD, Miles TS. Does induction of plastic change in motor cortex improve leg function after stroke? Neurology. 2003;61: ) Quartarone A, Rizzo V, Bagnato S, Morgante F, Sant'Angelo A, Girlanda P, Siebner HR. Rapid-rate paired associative stimulation of the median nerve and motor cortex can produce long-lasting changes in motor cortical excitability in humans. J Physiol. 2006;575: ) Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004;55: ) Ward NS, Brown MM, Thompson AJ, Frackowiak RS. Longitudinal changes in cerebral response to proprioceptive input in individual patients after stroke: An fmri study. Neurorehabil Neural Repair. 2006;20: ) Ward NS, Cohen LG. Mechanisms underlying recovery of motor function after stroke. Arch Neurol. 2004;61: ) Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA, Harris-Love M, Perez MA, Ragert P, Rothwell JC, Cohen LG. Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control. J Physiol. 2008;586: ) Butefisch CM, Netz J, Wessling M, Seitz RJ, Homberg V. Remote changes in cortical excitability after stroke. Brain. 2003;126: ) Butefisch CM, Wessling M, Netz J, Seitz RJ, Homberg V. Relationship between interhemispheric inhibition and motor cortex excitability in subacute stroke patients. Neurorehabil Neural Repair. 2008;22: ) Fregni F, Pascual-Leone A. Hand motor recovery after stroke: Tuning the orchestra to improve hand motor function. Cogn Behav Neurol. 2006;19: ) Hummel FC, Voller B, Celnik P, Floel A, Giraux P, Gerloff C, Cohen LG. Effects of brain polarization on reaction times and pinch force in chronic stroke. BMC Neurosci. 2006;7:73 102) Khedr EM, Ahmed MA, Fathy N, Rothwell JC. Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology. 2005;65: ) Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK, Hallett M. Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor 18

8 백남종 : 신경조절과뇌가소성 skill acquisition in chronic stroke. Stroke. 2006;37: ) Hummel F, Celnik P, Giraux P, Floel A, Wu WH, Gerloff C, Cohen LG. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005;128: ) Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, Rigonatti SP, Marcolin MA, Freedman SD, Nitsche MA, Pascual-Leone A. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 2005;16: ) Mansur CG, Fregni F, Boggio PS, Riberto M, Gallucci-Neto J, Santos CM, Wagner T, Rigonatti SP, Marcolin MA, Pascual-Leone A. A sham stimulation-controlled trial of rtms of the unaffected hemisphere in stroke patients. Neurology. 2005;64: ) Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, Wagner T, Fecteau S, Rigonatti SP, Riberto M, Freedman SD, Pascual-Leone A. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006;37: ) Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, Pascual- Leone A, Fregni F. Repeated sessions of noninvasive brain dc stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 2007;25: ) Kapur N. Paradoxical functional facilitation in brainbehaviour research. A critical review. Brain. 1996;119(Pt 5): ) Naeser MA, Martin PI, Nicholas M, Baker EH, Seekins H, Kobayashi M, Theoret H, Fregni F, Maria-Tormos J, Kurland J, Doron KW, Pascual-Leone A. Improved picture naming in chronic aphasia after tms to part of right broca's area: An open-protocol study. Brain Lang. 2005;93: ) Shindo K, Sugiyama K, Huabao L, Nishijima K, Kondo T, Izumi S. Long-term effect of low-frequency repetitive transcranial magnetic stimulation over the unaffected posterior parietal cortex in patients with unilateral spatial neglect. J Rehabil Med. 2006;38: ) Brighina F, Bisiach E, Oliveri M, Piazza A, La Bua V, Daniele O, Fierro B. 1 hz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans. Neurosci Lett. 2003;336: ) Oliveri M, Bisiach E, Brighina F, Piazza A, La Bua V, Buffa D, Fierro B. Rtms of the unaffected hemisphere transiently reduces contralesional visuospatial hemineglect. Neurology. 2001;57: ) Turrigiano GG, Nelson SB. Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol. 2000;10: ) Turrigiano GG, Nelson SB. Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci. 2004;5: ) Ziemann U, Ilic TV, Pauli C, Meintzschel F, Ruge D. Learning modifies subsequent induction of long-term potentiation-like and long-term depression-like plasticity in human motor cortex. J Neurosci. 2004;24: ) Siebner HR, Lang N, Rizzo V, Nitsche MA, Paulus W, Lemon RN, Rothwell JC. Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: Evidence for homeostatic plasticity in the human motor cortex. J Neurosci. 2004;24: ) Lang N, Siebner HR, Ernst D, Nitsche MA, Paulus W, Lemon RN, Rothwell JC. Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects. Biol Psychiatry. 2004;56: ) Quartarone A, Rizzo V, Bagnato S, Morgante F, Sant'Angelo A, Romano M, Crupi D, Girlanda P, Rothwell JC, Siebner HR. Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. Brain. 2005;128: ) Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M, Pascual-Leone A, Fregni F. Effects of transcranial direct current stimulation on working memory in patients with parkinson's disease. J Neurol Sci. 2006;249: ) Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A, Feredoes E, Marcolin MA, Rigonatti SP, Silva MT, Paulus W, Pascual-Leone A. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res. 2005;166: ) Osaka N, Otsuka Y, Hirose N, Ikeda T, Mima T, Fukuyama H, Osaka M. Transcranial magnetic stimulation (tms) applied to left dorsolateral prefrontal cortex disrupts verbal working memory performance in humans. Neurosci Lett. 2007;418: ) Marshall L, Molle M, Siebner HR, Born J. Bifrontal transcranial direct current stimulation slows reaction time in a working memory task. BMC Neurosci. 2005;6:23 19