J Neurosurg 115:971–984, 2011 Magnetic resonance imaging techniques for visualization of the subthalamic nucleus A review ELLEN J. L. BRUNENbeRG, M.SC.,1 BRAM PLATEL, PH.D.,2 PAUL A. M. HOFMAN, PH.D., M.D.,3 BART M. TER HAAR ROmeNY, PH.D.,1,4 AND VeeRLE VIsseR-VANdeWALLE, PH.D., M.D.5,6 1Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven; Departments of 3Radiology, 4Biomedical Engineering, and 5Neurosurgery, and 6Maastricht Institute for Neuromodulative Development, Maastricht University Medical Center, Maastricht, The Netherlands; and 2Fraunhofer MEVIS, Bremen, Germany The authors reviewed 70 publications on MR imaging–based targeting techniques for identifying the subtha- lamic nucleus (STN) for deep brain stimulation in patients with Parkinson disease. Of these 70 publications, 33 presented quantitatively validated results. There is still no consensus on which targeting technique to use for surgery planning; methods vary greatly between centers. Some groups apply indirect methods involving anatomical landmarks, or atlases incorporating ana- tomical or functional data. Others perform direct visualization on MR imaging, using T2-weighted spin echo or inver- sion recovery protocols. The combined studies do not offer a straightforward conclusion on the best targeting protocol. Indirect methods are not patient specific, leading to varying results between cases. On the other hand, direct targeting on MR imaging suffers from lack of contrast within the subthalamic region, resulting in a poor delineation of the STN. These defi- ciencies result in a need for intraoperative adaptation of the original target based on test stimulation with or without microelectrode recording. It is expected that future advances in MR imaging technology will lead to improvements in direct targeting. The use of new MR imaging modalities such as diffusion MR imaging might even lead to the specific identification of the different functional parts of the STN, such as the dorsolateral sensorimotor part, the target for deep brain stimulation. (DOI: 10.3171/2011.6.JNS101571) KEY WORDS • deep brain stimulation • targeting • subthalamic nucleus • MR imaging • functional neurosurgery EEP brain stimulation of the STN was introduced terioration and behavioral changes98 and have been re- as a treatment for advanced Parkinson disease ported in approximately 40%–50% of patients.89 It is hy- in 1993.69 Patients who initially showed a good pothesized that these side effects are the result of direct Dresponse to levodopa but suffer from on-off fluctuations stimulation of or current spread to the nonmotor parts of after a prolonged medication regimen have been shown the STN.88 In addition to a large dorsolateral motor part, to benefit from STN DBS. The beneficial effects of STN the STN has 2 other functional subterritories, namely a DBS on the motor symptoms of Parkinson disease have small ventromedial limbic part and a cognitive part inter- been described in long-term follow-up studies,74,95,96 but mediate in position and size.41,88 unwanted stimulation-induced side effects can occur. Precise targeting of the dorsolateral (motor) part of These side effects have been described as cognitive de- the STN is of great importance for 2 reasons: first of all, to obtain the best possible effect on motor symptoms, and second, to minimize the undesirable side effects on cog- Abbreviations used in this paper: AC = anterior commissure; 35,92 DBS = deep brain stimulation; FSE = fast spin echo; IR = inversion nition and behavior. Yet, the operative technique of recovery; MCP = midcommissural point; MER = microelectrode recording; MPRAGE = magnetization prepared rapid acquisition This article contains some figures that are displayed in color gradient echo; PC = posterior commissure; STIR = short tau inver- on line but in black and white in the print edition. sion recovery; STN = subthalamic nucleus; TSE = turbo spin echo. J Neurosurg / Volume 115 / November 2011 971 E. J. L. Brunenberg et al. STN DBS including the imaging method for primary tar- geting of the STN still varies greatly between centers.53 Magnetic resonance imaging is one of the most frequent- ly used modalities, alone or in combination with CT or ventriculography. 90 Most DBS procedures also involve a secondary targeting step using intraoperative assess- ments, such as MER or macrostimulation, to adapt the position of the electrodes to the clinical goals.17,30 The aim of this paper is to review the multitude of available methods and give a systematic overview of techniques for primary targeting of the dorsolateral part of the STN. This review discusses both indirect and di- rect targeting procedures, as well as comparative studies. The overall focus of the review is on MR imaging, be- cause this modality is most widely used. The next section of this paper will summarize indirect and direct targeting methods using MR imaging. Subsequently, the results of FIG. 1. Diagram showing AC-PC line–based targeting in a sagittal the systematic review will be presented. Finally, the ad- plane. After the AC and PC are identified, the midcommissural point vantages and drawbacks of the targeting techniques will (MCP) is determined. From there, the STN position can be calculated be discussed. using fixed distances (often 12 mm lateral, 3 mm inferior, and 3 mm posterior) based on an atlas. Summary of Targeting Methods An often used method is the T2-weighted FSE MR 81,83 Methods for targeting the dorsolateral STN can be imaging protocol, on which the STN shows as a hy- pointense area (see Fig. 5). Another popular technique for classified as either direct or indirect. Indirect methods 48 rely on contextual information, while direct methods fo- direct visualization is the IR protocol (see Fig. 6). Still cus on visualizing the STN itself on preoperative images. subject to more research are the use of relaxation time maps12 and susceptibility-weighted (T2*) imaging (see 33 Indirect Targeting Fig. 7), together with special postprocessing methods to reduce signal loss and enhance contrast. Indirect targeting can rely on 2 types of contextual information—patient-specific landmarks or generic atlas Systematic Review information adapted to the patient’s anatomy. The gold standard in indirect targeting using ana- In order to present a review on the different target- tomical landmarks involves the AC and PC.82 Once one ing methods, we performed a thorough search for papers has localized the AC, PC, and the midcommissural point, on STN targeting. The criteria that we used are briefly the stereotactic coordinates of the STN follow from fixed outlined below. distances based on classical atlases such as the Schalten- brand-Wahren brain atlas, as can be seen in Fig. 1.77 The Search Strategy second most widely used landmark is the red nucleus First, we searched PubMed and ScienceDirect for (Fig. 2).7,10 Less widespread methods include the use of papers published between January 1999 and January the nigrocapsular angle (as explained in Fig. 3),34 the 2011, using the terms “targeting,” “magnetic resonance supramammillary commissure,52 the postmammillary imaging,” “MRI,” or “visualization” in combination with commissure,91 and the line connecting the mammillary “subthalamic nucleus” or “STN.” Second, we explored bodies and the PC.73 the bibliographies of relevant publications until no fur- Furthermore, regions of interest can also be deter- ther additional studies were found. Papers were selected mined by mapping an anatomical and/or functional at- if they provided qualitative descriptions or quantitative las onto the patient’s MR imaging (see Fig. 4). Anatomi- results of direct or indirect MR imaging–based STN tar- cal atlases incorporate information about the position geting methods. Language other than English was an ex- of brain structures.62,76 The most popular ones are the clusion criterion. Talairach-Tournoux atlas,85 the Schaltenbrand-Wahren We included 70 publications, of which 33 stud- atlas,77 and the Montreal Neurological Institute atlas.22 ies quantitatively validated results of patient trials. The Functional atlases consist of point sets that are collected quantitative results are reported in Tables 1–4. The de- during MER, postoperative imaging or neurological as- tails extracted from the studies for this purpose included sessments.24,37,39,59,63 the following: number of subjects, targeting techniques used (landmark, MR imaging protocol, atlas, registration Direct Targeting method), validation method, outcome, and the main con- clusion. Direct targeting involves the use of specific MR im- aging protocols that enable direct visualization of the Indirect Targeting STN, avoiding the need to employ contextual informa- tion. Anatomical Landmarks. Publications on landmark- 972 J Neurosurg / Volume 115 / November 2011 Magnetic resonance imaging for STN visualization FIG. 3. Diagram showing targeting based on the nigrocapsular an- gle, in a sagittal plane. The STN lies in the corner that is formed by the descending internal capsule (IC) and the substantia nigra (SN). substantia nigra on MR imaging. Lee et al.52 proposed the supramammillary commissure, which lacked reliability. Toda et al.91 used the postmammillary commissure and selected the central electrode in 81% of cases. Finally, Rij kers et al.73 suggested the line connecting the mammil- lary bodies and PC, although this remains to be validated. Brain Atlas Registration. Table 2 summarizes the pa- pers found on atlas-based STN targeting that presented quantitative results. Ortega et al.62 digitized the anatomi- FIG. 2. Diagram showing red nucleus–based targeting in an axial cal Talairach-Tournoux atlas, registered it nonlinearly, plane. The center of the STN lies on the same line as the anterior and compared the resulting targets with recorded micro- boundary of the red nucleus (RN). electrode positions, obtaining good results. However, No- winski et al.60 demonstrated inconsistency of the 3 planes based targeting presenting quantitative results can be for an anatomical atlas in the STN region, restricting the found in Table 1. After the ventriculography-based study use of the atlas in 3D.