多模態神經導航輔助下的術中磁共振

在過去的十余年間，術中成像已成為神經外科熱點之一。在術中就能客觀地評估腫瘤的切除程度是非常有利的。如果術中發現有殘留，術者可繼續進行腫瘤切除。相對傳統方式術者主觀判斷來說，術中影像能夠提供更為客觀的術中評估信息，是一種很好的術中質量控制手段［1－6］。 除此之外，借助于計算機輔助外科，能夠同時進行神經導航［5，7，8］。導航系統使得術者對手術野術前和術中影像進行必要的聯系，從而實時反饋信息。而更重要的是，不僅術中影像能夠發現遺漏的殘留腫瘤，并使得術者進一步擴大切除范圍，還能夠借助術中導航來避免損傷腦重要結構，防止增加新的神經功能障礙。

在傳統導航系統（又稱為無框架立體定向導航）中，手術區域是與三維空間內的解剖影像相關聯的。顯微鏡下導航在實際使用中更具優勢。借助于現代顯微鏡的抬頭顯示器功能，導航影像能被疊加并投射在顯微鏡下的手術視野內。傳統的解剖結構導航在很多中心已常規使用，近年來，更逐漸演化至整合多種影像信息的多模態神經導航。

進行多模態神經導航的首要步驟就是開發功能神經導航，譬如將腦磁圖（MEG）［9－11］或功能磁共振（fMRI）［5，12］顯示的腦重要功能區（如語言區和運動區皮層）整合進導航系統，并生成個體化的導航計劃。功能神經導航的使用，使得在重要功能區更徹底地切除腫瘤，而不增加術后致殘率成為可能。彌散張量成像纖維束示蹤技術（DTI）整合進導航系統后，將功能神經導航的范圍擴展至皮層下區域［13－16］。 而整合 PET 或磁共振波譜（MRS）則使導航系統能夠根據腫瘤的代謝情況進行多模態神經導航［17－22］。

1 將導航整合進外科常規流程

神經外科手術室應該使手術者方便的獲取患者的資料和信息。多模態神經導航能夠借助于手術區域周邊的顯示器和手術顯微鏡內的投射影像顯示病人的多模態腦功能影像，是整合過程中的主要部分。

與傳統導航系統使用的觀察棒相比，顯微鏡下導航可以直接在手術野中觀察各重要結構。因為觀察棒只能在導航圖像上顯示其尖端，因此在術中進行導航時，術者常常需要將視線離開顯微鏡并觀察導航屏幕，中斷了正常的手術流程。而顯微鏡下導航具備的抬頭顯示功能可以將腦功能結構的信息以不同的顏色投射在手術視野內，與此同時，顯微鏡焦點或是手術器械尖端可以顯示在導航系統屏幕上。

盡管如此，現有的導航系統仍有很大的改進潛力。在大多數情況下，手術視野內顯示的是二維圖像，對手術視野內深度的立體結構顯示不佳，未來將有可能改進為視野內三維圖像。而目前常用的導航系統的圖像質量尚需提高。另外的一個重要問題是，導航系統應該避免因同時投射過多的影像資料而影響手術者的判斷。下一代的高級導航系統需要開發相應功能以使系統在不同的手術階段智能顯示相關的重要腦功能結構，以免誤導手術者或中斷正常的外科手術流程。

那么，在術中磁共振環境下的導航應該是什么樣的概念？一種方式是磁共振機本身就作為一個導航儀，如使用0.5T的GE磁共振機的系統，患者在磁體內接受手術，手術同時進行磁共振掃描。用此方式，手術時可以在磁共振圖像上實時觀察到手術器械的位置［1，23，24］。 這種導航方式基于實時磁共振成像，也被稱為實時立體定向，常被用來進行穿刺置管或是立體定向活檢［25－27］。

另一種術中磁共振和導航的整合概念是術中磁共振和導航不是同時進行。大多數系統將導航設備安放在磁體5高斯（5G）線外，以便能使用非磁共振兼容的標準手術器械進行手術。如果僅僅將普通導航系統放置于磁體附近有可能引起相關的安全事故，因此，吊頂式導航系統是一個比較好的選擇。整合術中影像和導航對于優化術中導航流程至關重要。術前、術中的影像學數據高效地傳輸至導航系統必不可少。優化排列術中成像序列的順序，以便充分利用時間，在進行磁共振掃描的同時進行導航計劃的更新。

在進行神經導航輔助腫瘤切除的過程中，導航信息的準確性是非常重要的。在所有可能導致導航誤差的因素當中，患者手術開始時的首次注冊最易導致誤差。目前最常用的導航注冊方法是在皮膚表面粘貼導航標記物，并以影像學方法顯示標記物，然后通過計算機注冊計算將標記物的實際空間位置與導航系統內虛擬位置相對應，完成注冊和配準的過程。自動注冊法由于無需操作者的操作，因此，可以減少操作者相關的注冊誤差［28］。

2 自動注冊

導航準確性受一系列因素影響，如操作誤差、注冊系統的移位、術中腦組織的變形（腦組織移位）等。操作誤差常見影響因素包括：影像系統成像質量，導航系統本身設備精度和患者注冊過程的質量［29］。磁共振成像過程中的影像變形常由成像過程中的化學位移和掃描物體的非勻質性產生［30］。對使用者來說，由此原因產生的導航誤差和導航系統技術缺陷產生的誤差很難被克服。因此，通過改進使用者的注冊操作和積累經驗是更為現實的減少導航誤差的方法。

有多種方法可以完成標準導航注冊。一方面，可以利用導航標記物（粘貼于皮膚表面或是釘入顱骨）或是頭部解剖部位進行注冊。另一方面，還可利用面部或頭部解剖輪廓進行注冊。多個研究［31－34］證實了上述注冊方法的可靠性，而借助于影像自動或半自動探測標記物技術，也可以比較快速地完成此類導航注冊［35］。盡管如此，上述注冊過程仍然需要人工進行操作，因此不僅費時，而且容易產生誤差。

雖然自動注冊的基本原理仍是基于空間位置的點對點注冊，但是它避免了使用點對點注冊時常規注冊方式容易產生誤差的環節。自動注冊的主要任務是將導航所用影像學數據與導航參考架關聯起來。參考架帶有反光標記物，并被剛性固定在手術頭架上，其作用是給導航系統追蹤手術器械提供一個參照物。從數學角度看，參考架和患者影像數據構成了兩個獨立的坐標系統。一個系統以參考架為基準，定位導航器械與參考架的空間相對位置。另一個系統則將導航器械的三維圖像投射在患者的影像圖像上，從而在屏幕上顯示在患者影像資料上的器械位置，或是將圖像投射在手術顯微鏡內，進行鏡下導航。

通常我們認為上述兩個坐標系統通過一個剛性配準系統關聯在一起，從而使這兩個系統通過旋轉和移位吻合在一起，或是將一個坐標系內的導航器械位置，轉化為另一坐標系內影像資料上的相應位置。為了達成上述目的，必須分別在實際空間內及影像資料上至少定義三個相應標記點。然后，點對應算法將選擇最優旋轉和移位參數，減少注冊誤差，并進行最優化注冊配準。這種標記點注冊法的一大改進是自動注冊法的引入。此法需使用自動注冊架，該器材由一系列位置相對固定的標記點和導航反光球組成。注冊架附加在磁共振上片射頻線圈上，并使各標記點盡量靠近患者頭部，以便進行磁共振成像時能顯示各標記點。掃描完成后，圖像資料被傳送至導航工作站，操作者僅需簡單調整導航紅外攝像頭，追蹤導航參考架和自動注冊架的反光球部分，然后導航系統即可計算出參考架和自動注冊架之間的空間關系。當自動注冊架的反光球空間位置確定后，自動標記物探測算法可以在影像圖像上定位出各個標記點。因為系統已內置了關于各個標記點確切位置和排列的空間位置信息，所以上述信息可直接被用來進行標記物配準注冊。綜合自動注冊架和導航參考架的相對位置，自動注冊架內各標記物的空間位置，以及各標記物在影像上和患者頭部的相對位置，通過計算，就可以定義患者頭部在空間的具體位置并開始導航。通常可在患者頭皮上放置一個額外標記物，并不將其列入注冊標記物，以便可以在注冊后，借助該標記物判斷注冊誤差（通常在0.3～2.5 mm之間）。而針對自動注冊系統進行的磁共振水膜測試證實該方法誤差為0.88～2.13 mm，與傳統方法的誤差相當。在大多數的測試中，自動注冊甚至比使用4或7個標記物的注冊方法精度更佳［28］。

3 多模態導航

降低術后并發癥的發生率至關重要，尤其是對于高級別膠質瘤來說。因為此類患者，擴大切除范圍往往只能延長數周生存時間，而術后長期的并發癥將嚴重影響患者的生存質量。因此，必須同時兼顧最大化的病灶切除和最大化的神經功能保護。術中成像不僅有助于術中最大化的切除病變，還能夠通過整合術中多模態神經功能導航來最小化神經功能損傷［13，36］。隨著外科技術和圍手術期技術的發展，現在已能夠對毗鄰重要功能區的惡性膠質腫瘤進行最大化切除而并不明顯增加術后致殘率。有關研究表明，大于98%的病變切除率將明顯延長惡性膠質腫瘤患者術后的生存時間，尤其是對Karnofsky評分較好的年輕患者而言［37］。

為達到上述目標，整合腦解剖和功能信息的功能神經導航是術中磁共振的良好補充。借助功能神經導航，可以避免過于激進的切除，并降低術后新發神經功能障礙的發生率。同時，將MEG和fMRI影像整合進功能神經導航系統有助于定位重要腦功能區，如運動區和語言區等［11-12］。

我們曾進行了一項回顧性研究，目的是評估腦磁圖對于膠質瘤切除決策的影響［9］。研究包括了5年內所有患有波及功能區的膠質瘤患者，共有191例，其中119例幕上膠質瘤。根據腦磁圖檢查的結果，約有26.8%的病例在術后有很大可能性發生神經系統嚴重并發癥，因此被認為不適合手術。該研究結果與另一項已發表的研究結果吻合。在該研究中，約30%（12／40例）的腫瘤或動靜脈畸形患者由于腦磁圖的結果而選擇了非手術治療［38］。當腦功能成像結果融合進無框架導航系統用于手術后，術后致殘率低至2.3%，而總體的致殘率為6.8%。與其他使用常規手段的研究（致殘率6%～31.7%）相比，上述數據說明了功能神經導航能夠降低術后的致殘率［39-43］。當然，我們也能將該數據解讀為，由于術前進行了全面細致的腦功能成像，從而使病例的選擇更為仔細和謹慎，使得術后致殘率降低。術前的腦功能成像對膠質瘤術前風險評估有幫助，而功能神經導航能降低術后致殘率。同時，運動區和語言區皮層的術前定位，也對臨床有很大指導意義［44-45］。

腦磁圖或功能磁共振只能定位腦皮層功能區。然而，在膠質瘤切除過程中，對腦深部結構，如重要白質纖維束的損傷，同樣能夠導致神經功能障礙。彌散張量成像技術，不僅能夠描繪腫瘤邊界，也能被用來顯示錐體束等白質纖維束。了解纖維束的走行及與腫瘤的解剖關系，對預防術后神經功能障礙很有幫助［46-47］。將DTI生成的纖維束圖像融合進導航系統指導手術可以實現術中對這些重要結構的保護［16，48－49］。但有一個重要前提，就是必須對術中腦解剖結構的變化 （亦稱為腦移位）加以考慮。和功能磁共振、腦磁圖相比，腦移位對DTI成像的影響更大，因為術中皮層結構的移位，能被直接觀察到，而手術創腔深部接近白質纖維束的地方，幾乎是不可能在直視下觀察到移位的。術中的DTI纖維束成像，顯示腫瘤切除過程中，纖維束有顯著的移位［15，50］。 因為纖維束的移位，術前的相關功能成像信息將不再準確，所以，只要腦移位沒有獲得補償，則術中導航將不再可靠。因此，在術中不僅有必要更新解剖影像，同時也需要更新腦功能影像。術中的DTI纖維束示蹤能夠顯示殘余腫瘤與重要白質纖維束的相對關系［15，50］。術中電刺激正中神經來進行被動刺激的功能磁共振則能顯示感覺區皮層［51］。

除了腦解剖和功能成像之外，還有一些其他影像數據可以用來進行多模態影像導航。如PET、磁共振波譜（MRS）和磁共振彌散成像能提供腫瘤邊界的信息。將代謝影像融合進導航系統能將代謝信息和病理信息進行關聯［52－53］。上述信息能否用于手術中，目前正在研究中。而新興技術，如磁共振分子成像，也許會在未來成為術中成像的手段之一。

4 導航更新

腫瘤切除、腦腫脹、腦壓板牽拉以及釋放腦脊液，都會引起術中的腦組織變形，又稱為“腦移位”［24，54］。 因此，如果單純依賴術前的影像學數據，導航系統的準確率在術中將下降。術中影像數據提供了術中補償腦移位的手段。借助于術中成像，能夠顯示術中的腦移位情況，同時也能顯示腫瘤切除程度［24，55－57］。 通過術中重新注冊來進行腦移位的補償，并更新導航計劃操作繁瑣［56－57］。 在我們使用低場強術中磁共振系統的臨床實踐中，必須在開顱骨窗周邊固定標記物，然后進行術中再注冊。然而，低場強術中MRI系統的圖像質量較差，從而使得在術中圖像上分辨這些標記物變得十分復雜。除此之外，更新導航計劃本身也很費時，因為上述標記物首先要被固定在骨窗周邊，然后再在術中MR圖像上辨認并將其標記出來，隨后再使用導航觀察棒逐個定位實際標記物，并將標記物的空間位置和影像上的位置一一對應起來 （亦稱為術中患者再注冊）。正因為上述繁瑣的操作，使得在我們進行的330例低場強術中磁共振手術患者中，盡管有26%的病例在進行術中成像時，發現有腫瘤殘留（如膠質瘤）且能被繼續切除，最終只有 16 例（4.8%）進行了真正的術中導航更新［56，58］。

高場強術中磁共振和顯微鏡下導航使得術中導航更新成為現實［5］。除了傳統的顱骨標記物方法之外，還有另外兩種方法可以進行術中患者再注冊，一個經過校準的注冊參考架可以固定在術中磁共振的上片線圈上，并能被導航系統追蹤［28］。在導航注冊前，先需要進行一次三維磁共振掃描，掃描范圍需包括整個參考架，以便參考架上的所有標記物能顯示出來并被用來進行注冊。同樣的過程也能用于術中再次注冊。此時，使用一個消毒的注冊參考架，將其與消毒的術中上片磁共振線圈連接，該方法也可作為其他注冊手段失敗時的后備方法。

如果不需要患者術中再注冊，術中的導航更新則更為簡單。首先將術中影像與術前影像進行剛性配準，然后描繪殘余腫瘤輪廓，最后恢復患者的初始注冊數據。這樣可以將原來的注冊空間坐標用于術中影像上來完成快速地術中影像注冊。術中更新導航數據能夠可靠地定位殘留腫瘤或修正穿刺導管位置。而鏡下導航則能夠在手術視野內快速準確地定位殘留腫瘤，有非常重要的作用。術后病理結果顯示，擴大切除的部分均為腫瘤組織，沒有假陽性的結果。這當然是由于殘留腫瘤被可靠地描繪出來并用來更新導航所致。而將術前和術中影像并列顯示也對影像判讀大有幫助，并且有效地減少了創腔邊緣手術痕跡對影像判讀的干擾。

通過將術中和術前的影像并列顯示，可以清楚顯示殘留腫瘤，也可以同時顯示腦移位程度。重復的解剖標志確認可以證實通過剛性配準，進行可靠的術中導航更新，而無需再次進行導航注冊。剛性配準注冊法不太容易受腦移位或是腫瘤切除的影響。這可以通過對比剛性配準后的比較固定的解剖位置來證實，比如對比眼眶和頭釘等。一項關于導航自動注冊的研究顯示，通過術中和術前影像的剛性配準，注冊誤差在2 mm以內［59］。當然，為避免發生嚴重注冊誤差，在進行剛性配準后，必須進行人工確認。

利用術中影像學資料更新導航是目前校正腦移位的最可靠方法。同樣的工作流程也可以用來更新多模態的腦功能數據。腦功能成像信息，如fMRI或DTI等可以在術中獲取并直接用于術中導航更新。當然，在實際臨床操作中，有時上述工作比較費時，如在顯像進行連接語言區的纖維束時。

另外，非線性配準及模式識別等更為復雜的技術有可能使包含腦功能信息的術前影像與術中磁共振影像融合配準［60，61］。該技術在無法進行高場強術中磁共振，但能進行其他形式的腦解剖成像時可能會很有幫助。因為此時，可以將術前的多模態腦功能數據與術中獲得的較低質量的腦解剖數據進行非線性注冊配準，從而預測腦功能結構在術中的位置。一個比較好的替代手段是術中超聲，尤其是術中 3D 超聲［62－64］。 當然，使用術中超聲等其他替代手段能否清晰顯示膠質瘤切除范圍目前尚存在爭議。但是，作為一種真正的術中實時成像方法，術中超聲可以提供術中解剖影像，從而能將術前腦功能影像通過非線性配準變形后，來顯示術中腦功能結構位置，抵消腦移位的影響。此時，術前的磁共振影像根據非線性配準生成的腦移位數學模型進行相應的形變，從而反應術中腦功能結構的移位［65－69］。

關于使用數學模型來模擬腦移位，目前尚無法準確預測術中的實際情況。術中的多種因素，如腦室系統開放，患者體位變動或腦水腫等，都可能影響腦移位的程度和方向。然而，數學模型加上術中的部分三維影像數據，則有可能調整術前影像來反映術中移位［67，69－71］。術中高場強磁共振，結合術中解剖和腦功能影像是驗證和改進這些數學模型的最佳工具。

5 結論

融合了多模態腦功能成像的鏡下導航技術和術中高場強磁共振，是目前最有希望做到最大程度切除腫瘤且最大程度保留神經功能的方法之一。多模態神經功能導航融合了腦常規解剖，功能及代謝信息。定位殘留腫瘤，分辨腫瘤周邊的重要功能結構，以及將影像信息與病理結果關聯是多模態功能神經導航的主要目的。利用術中影像資料更新導航后，可以修正腦移位的影響，并準確地定位殘留腫瘤。

同英文版）

（中國人民解放軍總醫院 陳曉雷譯）

doi：10.3969 ／j.issn.1002－0152.2012.04.002

Department of Neurosurgery，University Marburg，Marburg，Germany

Intraoperative imaging has attracted increasing interest in the last decade.The ability to objectively determine the extent of tumour removal during surgery is highly advantageous.If the resection is incomplete，one can attempt to remove the tumour residues that were initially missed during the same operation.In contrast to a subjective estimation by the neurosurgeon，intraoperative imaging allows an objective evaluation of the intraoperative situation，thus acting as quality control during surgery［1－6］.In addition to intraoperative imaging，an integral part of our concept of computer aided surgery is the possibility to apply navigation simultaneously［5，7，8］.Navigation allows essentially visualizing the results of pre-and intraoperative imaging in the surgical field，so that the image data provide an immediate feedback.The most important aspect is to prevent increased neurological deficits despite increased resections that might result from the attempt to remove initially overlooked tumor remnants that are detected by intraoperative imaging.

In standard navigation，also known as frameless stereotaxy，the real space of the surgical field is registered to the 3-D image space，which is based on anatomical data only.We prefer the application of microscope-based navigation，where the extent and localization of a tumour is superimposed on the microscope field of view through contours using the headsup display technology of the modern operating microscopes.Standard navigation based on anatomical information only，which has become a routine tool in many neurosurgical departments，was developed further by the integration of further information from other modalities resulting in the so-called multimodal navigation.

A first step in the direction of multimodal navigation was the development of functional navigation，where preoperative data from magnetoencephalography（MEG）［9－11］and functional magnetic resonance imaging （fMRI）［5，12］defining localizations of cortical eloquent brain areas，such as the motor and speech areas，in individual patients，were integrated in the navigation setup.This method of functional neuronavigation allowed more a thorough resection of tumours in risk zones with low morbidity.Integration of diffusion tensor imaging （DTI） data delineating the course of major white matter tracts extended this concept also to subcortical areas［13－16］，while the co-registration of PET data and information from MR spectroscopy （MRS）added metabolic information leading to true multimodal navigation［17－22］.

1 Implementation of navigation in the surgical workflow

The neurosurgical operating room should be the integrative place where all patient data can be visualized in a surgeon-friendly fashion.Multimodal navigation with the visualization of multimodal data on several screens close to the surgical site，as well as，the parallel superimposition of the relevant structures visualized by contours in different colours in the microscope field of view，is the main tool to achieve this integration.

In contrast to pointer-based navigation，microscope-based navigation provides a more intuitive data visualization directly in the surgical field.Pointer-based systems only delineate the position of an instrument，e.g.typically the tip of a pointer，in the image space，so that during surgery when navigation information is needed the surgical workflow is interrupted by necessitating that the surgeon is looking away from the surgical field to a navigation screen.Microscopebased navigation has the advantage of heads-up displays superimposing additional information on the surgical field by colour contours or semi-transparent 3-D objects，while in parallel still the position of an instrument，e.g. the autofocus position of the microscope is still additionally displayed on the navigation screen.

However，there is still much room for further enhancements of these display technologies.In most setups there is only a 2-D visualization，lacking real depth information，which would be possible in a real 3-D image injection setup.Also the realtime rendering of the displayed objects in the current standard commercial systems does not represent what is nowadays possible with near photo-realistic visualizations in other fields of computer graphics.One of the most important aspects in such systems is to avoid a confusion of the neurosurgeon by a potential information overload.Sophisticated systems have to be developed that present the most relevant information at a certain stage of surgery without impeding the surgical workflow and without distracting the neurosurgeon from his main task.

What are the navigation concepts in an intraoperative MR environment？ Either the MR scanner serves as a navigational device per se，as it was the basic principle in the 0.5T double-doughnut GE scanner concept，where the patient was operated directly in the scanner，so that surgical space and imaging space were identical，so that an instrument in the surgical space could be tracked in image space without much additional effort［1，23，24］.Direct navigation in the MR scanner is often based on realtime imaging，like in the so-called prospective stereotaxy，a method for trajectory alignment for placements of catheters or sampling biopsies［25－27］.

Other attempts to integrate intraoperative MRI and navigation result in a classical navigation setup because image space and surgical space are not identical，so that some kind of patient registration has to be applied.Most setups implement navigation at the 5 G line，so that standard non-MR-compatible instruments can be used.Ceiling mounted solutions of the navigation camera and screens［5］are an optimal solution in the intraoperative scenario，since just placing a standard navigation system close to an MR scanner increases the risk of potential magnetic accidents.To optimize the navigation workflow a close integration of imaging and navigation is necessary.For pre-and also intraoperative registration an efficient data transfer between scanner and navigation computers is mandatory，as well as an optimized order of the different imaging sequences allows navigation planning and preparation，while scanning is still going on.

High navigation accuracy is a prerequisite if the navigation information is to be used at critical steps during the resection of a tumor.Among all errors contributing to the overall navigation accuracy，the initial patient registration process is mostly prone to errors.The most common strategy for patient registration relies on placement of skin-adhesive fiducials，which can be detected in the images，so that their position in virtual and real physical space can be correlated to define the registration coordinate system.Automatic registration setups，allowing an user-independent registration of patient space and image space，try to reduce the user dependent errors［28］.

2 Automatic registration

Navigation accuracy is influenced by a variety of factors，among them are the so-called application accuracy，factors relating to a unwanted movement of the registration coordinate system （positional shift），and intraoperative events like brain deformation，which is known as brain shift.The application accuracy is influenced by the quality of imaging，by the technical accuracy of the system itself，and by the quality of patient registration，which defines the process of registering image space and real／surgical space［29］.While the spatial distortion of MR images，which is due to gradient field non-linearities and resonance offsets（chemical shifts and magnetic field inhomogenities）［30］，and the technical accuracy of the navigation system are not easily influenced by the user，the patient registration process is much user-dependent and is influenced by the individual registration strategy and user experience.

Standard patient registration can be achieved in different ways.On the one hand there are “marker-fit”-techniques using either extrinsic markers（so-called fiducials either self-adhesive or implanted in the skull bone） or anatomical landmarks for registration.On the other hand there are “surface-fit”-techniques using the outer contour of the face and the skull for the referencing process.Several studies［31－34］showed the reliability of these registration methods and rapid progress was made towards automatic marker detection in image space and a semiautomatic registration［35］.Nevertheless，the registration process itself still has to be performed manually and therefore remains time-consuming and prone to error.

The concept of an automatic registration is based on paired point registration but sparing the user all the error prone steps associated with it.The main task of the automatic registration is to create an unambiguous relationship between the reference array and the acquired images used for navigation.The reference array is an important reflective marker structure rigidly attached to the patient head via the head clamp.It is used as a relative reference for the system to be able to track instruments，even when the stereoscopic camera is moved into a different position.Looking from the mathematical standpoint the reference array and the volumetric images span two independent coordinate systems.One coordinate system is used to describe the position of tracked instruments in the surgical field or relative to the reference array，the other to render a 3-D model of the tracked instrument in the volumetric images，which in return then is projected on a 2-D view on a screen，or superimposed in the operating microscope，allowing the user to navigate on the images.

It is generally assumed that these two coordinate systems relate to each other via a rigid transformation matrix，describing the rotation and translation between these coordinate systems，or how to transform one position of the instrument，in the surgical space into a corresponding position in the virtual／image space.In order to be able to calculate the rotation and translational parameters，at least 3 points in the patient space and corresponding points in the virtual space have to be defined.A paired point matching algorithm then optimizes the rotation and translational parameters to minimize the root-mean-square-error between these point pairs or even to permute the pairs to achieve an optimal result.An additional indirection for fiducial registration is of importance to implement the automatic registration method.A so-called registration matrix is introduced，which already contains a fixed constellation of fiducials relative to a reflective marker structure，making it possible to use the registration matrix as a tracked instrument.The registration matrix is attached to the upper part of the head coil，so that the fiducials from the registration matrix are automatically imaged，when placed close enough to the patient’s head.Once the scan is completed and the acquired images are transferred to the navigation system，the user only has to adjust the navigation camera so that it can identify the reflective marker structure of the registration matrix and the reference array for a brief moment，so that the navigation system can determine the spatial relation between registration matrix and reference array.Once the acquisition of the reflective marker structures has been completed，an automatic marker detection algorithm detects the fiducials from the registration matrix in the image data set.Since the system knows the exact arrangement and position of the fiducials integrated in the registration ma-trix this information can be used as input for the paired point matching algorithm.Combining the information where the registration matrix was in relation to the reference array and how the detected fiducials in the images relate to the fiducials of the registration matrix and also knowing how the fiducials from the registration matrix relate to the spatial position of the matrix itself by the defined construction，a transforma-tion matrix can be calculated directly relating the refer-ence array with the acquired images，so that then the relation between image space and physical／surgical space is defined and navigation can be used.An additional skin fiducial that is not used for the registration process is localized after patient registration to docu-ment a target registration error，which is typically in the range between 0.3 and 2.5 mm.Phantom studies resulted in median localization errors between 0.88 and 2.13 mm for the automatic registration approach，which was at least not worse，in most test series even signifi-cantly better，than that of the standard registration no matter whether 4 or 7 fiducial markers were used［28］.

3 Multimodal navigation

Low postoperative neurological deficits are mandatory，especially in surgery of high grade tumors it is of no benefit for the patient to maximize the extent of a resection to potentially increase the survival time by only some weeks，when risking permanent neurological deficits right after surgery.It is absolutely mandatory to combine the goal of maximum resection with the goal of preservation of function.Intraoperative imaging helps not only to maximize the extent of resection but in combination with functional multimodal navigation also minimization of postoperative neurological deficits is possible［13，36］.With the advances in surgical techniques and perioperative technology，it is now possible to maximally resect malignant intrinsic glial neoplasms，even close to functionally critical areas，without increased morbidity. Studies have demonstrated a survival advantage of these lesions with a resection extent of 98%or greater，particularly in younger patients with good Karnofsky scores［37］.

To achieve this，functional navigation，i.e.integrating functional data into anatomical navigational datasets，is an important add-on to intraoperative MRI since it prevents too extensive resections，which would otherwise result in new neurological deficits.Meanwhile，data from MEG and fMRI are routinely integrated in functional navigation allowing identification of eloquent brain areas such as the motor area and speech related areas［11，12］.

In a retrospective study we focused on how the decision to resect a glioma was influenced by MEG［9］.In a time period of 5 consecutive years we have investigated every patient proposed for surgery，who harboured a lesion adjacent to an eloquent brain area.Altogether 191 patients were examined，119 of them harboured supratentorial gliomas.About every forth patient （26.8%） yielded a severe possible danger of postoperative neurological morbidity according to MEG and thus was not considered being a good candidate for surgery.This is a corresponding result to published data where 12 out of 40 investigated patients （30%）with tumours and vascular malformations underwent non-surgical therapy according to the MEG results［38］.When functional data were used in combination with frameless stereotactic devices the postoperative morbiditywasaslowas2.3%.Overallmorbidityhoweverwas 6.8%.These data reflect the beneficial effects of functional navigation in comparison to data of other studies with morbidity rates varying from 6 to 31.7%［39－43］.These figures can also be interpreted as a result of a more careful patient selection through the help of preoperative brain mapping.Preoperative identification of eloquent brain areas has an impact in the risk evaluation in glioma surgery，as well as functional navigation reduces the risk for postoperative neurological deficits.Besides identification of the motor strip，the localisation of language areas is of great clinical impact［44，45］.

Functional data from MEG and fMRI only localize function at the brain surface.However，neurologi-cal deficits can also occur during tumor resection due to damaging of deeper structures，such as major white matter tracts.DTI can be used not only to delineate tumor borders，but also to display the course of white matter tracts，such as the pyramidal tract.The knowledge of the course of major white matter tracts in relationship to a tumor helps to prevent new postoperative neurological deficits［46，47］.Registration of diffusion data with the navigational dataset［16，48，49］facilitates the intraoperative preservation of these eloquent structures.A prerequisite is that intraoperative changes of the brain anatomy，known as brain shift，are taken into account.In contrast to the use of fMRI and MEG，brain shift clinically effects much more the DTI data，because the intraoperative shifting of cortical areas during surgery can be well detected by the naked eye，however changes in the depth of a resection cavity，close to major white matter tracts，is nearly undetectable for the neurosurgeon during tumor resection.Intraoperative DTI，revealed a marked shifting of the pyramidal tract due to tumor resection［15，50］.As a consequence of this shifting the preoperative functional data are no longer valid，so navigation can no longer relied on，if this shifting is not compensated for.Therefore，it is necessary that not only intraoperative anatomical data are used to compensate for the effects of brain shift but also functional data have to be updated.Intraoperative acquisition of DTI data enables intraoperative fiber tracking to visualize how a tumor remnant is localized in relation to major white matter tracts［15，50］.Even intraoperative fMRI applying electrical stimulation of median and tibial nerves as a passive stimulation paradigm is possible and enables identification of the somatosensory cortex［51］.

Besides functional and structural data further information is available for a multimodal navigation setup.PET，MRS，and diffusion weighted imaging may provide information on the diffuse tumor border.Integration of metabolic maps into the navigation datasets enables a spatial correlation of metabolic data and histopathological findings［52，53］.Whether these techniques can also be used intraoperatively，so that these data can also be updated，is under investigation.Furthermore，upcoming techniques such as MR-based molecular imaging may find its role in the intraoperative imaging armamentarium.

4 Navigation updating

Tumor removal，brain swelling，the use of brain retractors，and cerebrospinal-fluid drainage all result in an intraoperative brain deformation，which is known as brain shift［24，54］.Thus，navigation systems relying on preoperative image data only have a decreasing accuracy during the surgical procedure.Intraoperative imaging offers a possibility to compensate for the effects of brain shift，because it provides a virtual reproduction of the actual intraoperative physical reality，on how the brain is deformed and on the achieved extent of tumor removal［24，55－57］.Compensation for brain shift by intraoperative registration of the intraoperative MRI data to update the navigation setup has been a cumbersome process［56，57］.In our low-field MRI setting bone fiducial markers had to be placed around the craniotomy opening，which were then used for intraoperative patient re-registration.With the restricted image quality of the low-field MRI system it was quite complicated to identify these markers in the intraoperative images.Furthermore，updating was a time consuming process，because these bone fiducials had to be placed around the craniotomy opening； then they had to be identified and marked in the intraoperative images and then they had to be individually identified in physical space using the tip of a pointer and correlated to the position in the intraoperative images to define the navigation coordinate system，i.e.intraoperative patient re-registration.This is the main reason why only in 16 out of 330 patients investigated with low-field MRI an actual navigation update was performed，despite intraoperative imaging had detected tumor remnants e.g.in the gliomas that could undergo further resection in about 26%［56，58］.

The setup integrating high-field MRI and micro-scope-based navigation offered to facilitate this intraoperative update procedure［5］.Besides the bone-fiducial placement for intraoperative re-registration two alternative patient registration methods and thus update strategies are available.A calibrated registration matrix can be attached to the upper part of the head coil and tracked by the navigation system.28 This automatic registration matrix can be used for an initial patient registration.Before the patient registration it is required that the anesthetized patient gets a preoperative 3-D MR scan after head fixation，which fully covers the registration matrix，so that all markers integrated in the registration matrix are visible and can be detected and used for registration.This approach is also a possibility to perform a registration of intraoperatively acquired images.A sterile registration matrix has to be connected to the sterile upper part of the head coil before it is attached to the head holder.This method serves as a backup approach if other registration strategies fail.

Navigation updating without an intraoperative patient re-registration is an even more straightforward approach.It is based on a rigid registration of the intraoperative image data with the preoperative image data，subsequent segmentation of the tumor remnant，and final restoring of the initial patient registration，so that the registration coordinate system of the preoperative image data is applied on the intraoperative images，allowing an immediate intraoperative image update.Updated image data allow a reliable identification of a tumor remnant or correction of a catheter.Microscope-based image injection with the direct visualization of the segmented tumor remnant in the surgical field plays a crucial role in the precise localization and orientation in the resection cavity.Histological analysis of the extended resections proved pathological tissue in all cases； there were no false positive findings.This is of course due to the fact that only areas of reliably identified tumor remnants were segmented and used for updating.The side-by-side analysis of preand intraoperative images greatly facilitates image interpretation and to exclude misinterpretations due to surgically induced changes at the resection border.

After updating also a side-by-side display of preand intraoperative images visualizing the segmented tumor remnant in both of them，is possible，facilitat ing orientation and image interpretation-therefore，also the extent of brain shift is easily visible.Repeated landmark checks have proved that the rigid registration approach is a reliable approach to update the navigation system without a repeated patient registration.The rigid registration algorithm is robust enough to accomplish a registration that is not sensitive to the effects of brain shift and the actual reduction of the tumor mass.This could be shown by analyzing the registration accuracy of structures that are not affected by brain shift，such as the position of both orbits and the position of the skull fixation pins.An extensive analysis comparing the automatic registration，which is used to register pre-and intraoperative images，with an independent reference registration showed，that the registration error is below 2 mm even in a worst case scenario［59］.Nevertheless，to prevent a mis-registration a visual control after rigid registration of pre-and intraoperative images is mandatory.

Updating the navigation system with intraoperative MR image data seems to be the most reliable method to compensate for the effects of brain shift.In contrast to previous setups this framework is also open to update multimodal information.Functional data，such as fMRI or DTI data can also be acquired intraoperatively and directly used for intraoperative updating，which in the clinical routine might be a time-consuming effort，especially when in case of e.g. visualization of speech connecting fiber tracts some sophisticated time-consuming non-standard tracking algorithms have to be applied.

Alternatively either non-linear registration techniques，as well as sophisticated techniques from pattern recognition analysis may allow a matching of preoperative MR data sets containing functional information with intraoperative MR image volumes［60，61］.This might also be a possibility in case where intraoperative MRI is not available，but other imaging modalities provide intraoperative 3-D information about the brain configuration，so that high-resolution multi-modality data can be registered non-linearly onto the ‘low-quality’ intraoperative data.An alternative to intraoperative MR imaging might be intraoperative ultrasound，especially intraoperative 3-D ultrasound［62－64］.Whether the image quality to evaluate the extent of a glioma resection is equivalent among the different imaging modalities is still discussed controversially.However，it is out of doubt that intraoperative ultrasound has the advantage of being a real-time modality.Ultrasound data may provide information on how to deform high-quality preoperative MR image data in order to represent the intraoperative real situation，thus compensating for the effects of brain shift.This approach relies on the non-linear registration of intraoperative ultrasound data with preoperative MR volume data.Consecutively the MR data are deformed using a mathematical model describing the deforma tion of the brain during surgery［65－69］.Mathematical models trying to simulate brain shift behavior will not be able to predict the actual intraoperative situation without further data.Intraoperative events such as opening of the ventricular system and CSF drainage，patient positioning，and brain swelling all influence the extent and direction of brain shift. However，mathematical models together with some sparse data describing the actual intraoperative 3-D situation may be able to adjust high-quality preoperative data to represent the intraoperative reality［67，69－71］.Intraoperative high-field MRI with anatomical and functional imaging possibilities is the ideal tool to validate and refine these models.

5 Conclusion

Microscope-based navigation serving as a common interface for the presentation of multimodal data in the surgical field in combination and close integration with intraoperative high-field MRI seems to be one of the most promising setups allowing avoiding unwanted tumor remnants while preserving neurological function.Multimodal navigation integrates standard anatomical，structural，functional，and metabolic data.Visualizing the initial extent of a lesion，identification of neighboring eloquent brain structures，as well as allowing a direct correlation of histology and multimodal data are the main tasks of navigation.After intraoperative imaging navigation data can be updated，so that brain shift is compensated for and initially missed tumor remnants can be localized reliably.

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