Neuromodulation: Technology at the Neural Interface Received: February 4, 2014
Revised: July 8, 2014
Accepted: July 24, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12238
Deep Brain Stimulation for Essential Tremor: Targeting the Dentato-Rubro-Thalamic Tract? Juergen Schlaier, PhD*; Judith Anthofer, MD*; Kathrin Steib, MD*; Claudia Fellner, MD†; Eva Rothenfusser, MD‡; Alexander Brawanski, PhD*; Max Lange, MD* Objective: The aim of our study was to evaluate the influence of the stimulation site relative to the dentato-rubro-thalamic tract (DRTT) on the alleviation of tremor in deep brain stimulation. Methods: Ten DRTTs in five patients were investigated using preoperative diffusion tensor imaging (DTI). Regions of interest for fiber tracking were located in the cerebellar dentate nucleus, the superior cerebellar peduncle and the contralateral red nucleus. The position and distance of all intraoperative stimulation sites to the DRTT were measured and correlated to the amount of tremor reduction. Results: Nine of 10 DRTTs could be identified using DTI-based fiber tracking. Better tremor reduction was achieved in locations in or posterior and lateral to the DRTT than in medial and anterior positions (p = 0.001). Stimulation sites inferior to and in the DRTT achieved better results than locations superior to the DRTT (p < 0.05). The vicinity of the stimulation site to the DRTT did not correlate with tremor alleviation. Discussion: In deep brain stimulation targeting for thalamic stimulation sites is limited to statistical, atlas-based coordinates. Diffusion tensor imaging and fiber tracking was used to visualize the dentato-rubro-thalamic tract as a potential, individualized target structure. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. DTI sequences with a higher number of read-out directions, probabilistic fiber tracking and three Tesla MRI scanners may lead to different results in the depiction of the chosen fiber tract and may provide a better correlation with stimulation effects. Conclusions: The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences, and fiber tracking algorithms are mandatory. Keywords: DBS, DRTT, DTI, electrode placement, essential tremor, MRI, VIM Conflict of Interest: Dr. Schlaier has received teaching honoraria from Medtronic, Inc. and research support from the following companies: St. Jude Medical, Antisense Pharma and Medtronic. He gave several talks in the last several years, which were partly sponsored by Medtronic, St. Jude Medical, or BrainLab. He also serves as a consultant to Medtronic, Inc. and receives compensation for these services. Dr. Anthofer has received travel grants and training fees for educational courses in functional neurosurgery from Medtronic. Dr. Steib has received travel grants and training fees for educational courses in functional neurosurgery from Medtronic and St. Jude Medical. Dr. Fellner reports no conflict of interest. Dr. Rothenfusser received fees for serving as a speaker in courses sponsored by Ipsen and Merz. Dr. Brawanski reports no conflict of interest. Dr. Lange has received fees for serving as a speaker, a consultant, and an advisory board member for Medtronic and UCB, and he has received research funding from UCB and St. Jude Medical.
INTRODUCTION
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Address correspondence to: Max Lange, MD, Neurosurgery, University of Regensburg, Medical Center, Franz-Josef-Strauss-Allee 11, 93049 Regensburg, Germany. Email: [email protected] * Department of Neurosurgery, Medical Center, University of Regensburg, Regensburg, Germany; † Institute of Radiology, Medical Center, University of Regensburg, Regensburg, Germany; and ‡ Department of Neurology, Medical Center, University of Regensburg, Regensburg, Germany For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Financial support: The authors received no financial support for the study.
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Deep brain stimulation has become a well-established treatment option for patients suffering from essential tremor (1,2). Most centers focus on the nucleus ventralis intermedius (Vim) as the target of choice for planning the trajectory of the electrodes (3,4). On conventional MR sequences it is impossible to discriminate the Vim from the neighboring subnuclei of the thalamus. Therefore, the majority of neurosurgeons relies on probabilistic coordinates, derived from investigations of a limited number of postmortem human brains. As has been shown by several groups, the inter-individual, anatomical variability of target regions in deep brain stimulation is quite considerable, so the reliability of atlasbased coordinates may be insufficient (5–8). Spiegelmann et al., as well as Vassal et al., suggested special MR sequences on three
SCHLAIER ET AL. Tesla or 1.5 Tesla scanners to visualize the Vim directly on the images that are used for planning (1,9). Fiber tracking based on diffusion tensor imaging seems to represent another possibility to determine the target region. As suggested by Coenen et al. the visualization of the dentato-robro-thalamic tract (DRTT) might help to individualize targeting in patients with essential tremor (10). The aim of this study was to evaluate the amount of tremor reduction depending on the electrode position relative to the DRTT.
Table 1. MRI-Parameters. T2 sagittal
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T2 axial
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T1 sagittal mp-rage
MATERIAL AND METHODS
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In this retrospective, clinical study we included 5 patients (2 female, 3 male) with essential tremor, who consecutively underwent bilateral VIM-stimulation. Patient age ranged from 53–73 years (mean: 61.4 years). The duration of the disease from the first diagnosis to the operation ranged from 2 to 27 years (mean: 12.4 years).
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DTI
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Inclusion Criteria for DBS Patients with essential tremor and pronounced tremor-related functional disability in daily life despite optimal medical treatment were included. Exclusion Criteria for DBS Exclusion criteria were age >75 years, dementia, severe frontal lobe disturbances, insufficient compliance, coagulopathies, immunosuppression and tremors other than essential tremor. If MR images showed pronounced cerebral atrophy and signs of severe cerebral macroangiopathy, patients were excluded as well. Preoperative Planning All MRI scans for target and trajectory planning were performed under general anaesthesia. In all patients the MRI scan (1.5 Tesla; Avanto, Siemens, Erlangen, Germany) was performed separately from the stereotactic CTscan (Sensation 16, Siemens, Erlangen, Germany; CRW, Radionics, Burlington, MA). MR imaging included T2 weighted sagittal images for the detection of the anterior (AC) and posterior commissure (PC), T2 weighted axial images for the detection of the Vim target according to AC-PCrelated coordinates (see below), volumetric T1-weighted MRI, mp-rage for trajectory planning and diffusion tensor imaging (DTI) for fiber tracking of the DRTT (Table 1). CT imaging was performed with 2-mm slice thickness reaching from the foramen magnum to the vertex without gantry tilt. All acquired images were transferred to a computer workstation where all data sets were fused to the volumetric T1-weighted MRI (iPlan Stereotaxy 3.0, BrainLab, Feldkirchen, Germany). The coordinates of the anterior (AC) and posterior commissure (PC) were determined on the sagittal T2-weighted images and checked for accuracy on the volumetric T1-weighted slices.
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Fibertracking Deterministic fibertracking was performed using iPlan stereotaxy software (Brainlab, Feldkirchen, Germany). The Dentato-RubroThalamic Tract was obtained by selection of fibers passing through three regions of interest as suggested by Kwon and his colleagues 2011 (11) (Fig. 1a–c): www.neuromodulationjournal.com
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TR 3030 msec, TE 120 msec, turbo spin echo (tse) voxel size 0.9 mm × 0.7 mm × 2 mm distance factor 0.2 mm acquisition time, 3:43 min TR 4070 msec, TE 80 msec, spin echo (se) voxel size 1 mm × 1 mm × 2 mm no distance factor parallel to the intercommissural plane acquisition time 34:49 min double dose (0.2 mmol/kg bodyweight) Gadobutrol voxel size 0.9 mm × 0.9 mm × 1.1 mm slice orientation sagittal TR 1680 msec, TE 2970 msec, α (flip angle) 15° matrix 256 × 256, FOV 240 mm acquisition time, 7:55 min spin-echo echo-planar imaging pulse sequence number of gradient directions 12 3 mm slice thickness; 39 slices TR 5700 msec, TE 98 msec, PAT2 field of view, 230 mm matrix, 128 × 128 b value, 1000 sec/mm2 acquisition time, 4:01 min
• the dentate nucleus cerebelli contralateral to the VIM of interest • the superior cerebellar peduncle contralateral to the VIM of interest • and the ipsilateral red nucleus Minimal fiber length was set to 30 mm and we worked with a fractional anisotropy level of 0.15.
Atlas-Based Targeting Atlas-based targeting of the VIM was performed according to the suggestions of Osenbach and Burchiel (12): • ant/post: 25% of the intercommisural line (IC) anterior to the posterior commisure (PC) • laterality: 13–15 mm lateral to IC ○ (11 mm lateral to lateral wall of III. ventricle, if width of III. ventricle > 6 mm) • sup/inf: same axial slice as IC The trajectories of the electrodes were planned on volumetric T1-weighted MPRage contrast-enhanced images and controlled on CT slices after fusion. Four additional trajectories (anterior, posterior, lateral and medial) were planned at 2 mm distance to the center trajectory to simulate the path of the five possible electrodes, according to the configuration of the “ben-gun” manual microdrive (Medtronic, Minneapolis, MN). In all cases a frontal burr hole close to the coronal suture was planned. All trajectories had to avoid sulci, ventricles and white matter blood vessels. Trajectories were rejected, if they came too close ( 0.05).
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THE DRTT IN ET-DBS
Table 2. Positions of the Stimulation Sites Relative to the DRTT and the Corresponding Extent of Tremor Alleviation. Position
N
Extent of tremor alleviation (%) Mean Standard deviation
Inside DRTT Anterior Posterior Medial Lateral Inferior to the horizontal segment Superior to the horizontal segment
8 18 19 4 9 23 15
81.25 61.67 83.90 25.00 85.56 83.70 48.33
11.57 29.85 25.23 35.36 24.17 23.07 27.50
We further investigated the extent of tremor reduction dependent on the distance to the DRTT at 1 mA, 2 mA and 3 mA amplitudes of current. Again, we did not find statistical significant correlations for any of the amplitudes of current. By looking only at the stimulation sites located posterior to the DRTT we did not find better tremor alleviation in positions closer to that tract than in remote positions (p = 0.526, ANOVA on ranks). The same held true for all the other locations: anterior (p = 0.155), lateral (p = 0.531), medial (p = 0.141), inferior (p = 0.762) and superior (p = 0.645). In summary, better tremor reduction was achieved in locations directly inside the DRTT and in the quadrant posterior, inferior and lateral to it in comparison to anterior, medial and superior positions. The distance of the stimulation site to the nearest fiber of the DRTT had no influence on tremor alleviation.
DISCUSSION In deep brain stimulation for essential tremor the nucleus Vim is the target used most frequently (3). Targeting is mainly based on atlas-derived coordinates resulting from investigations of a limited number of brains of human corpses. It has been shown for the Vim and other targets that due to inter-individual, anatomical variations the atlas-based targeting is not perfect (5–8,15). Efforts have been undertaken to delineate the Vim directly on special MR sequences on 1.5 T and 3 T scanners (1,9). Other groups have used diffusion tensor imaging and fiber tracking to directly or indirectly visualize the target region in the ventro-lateral thalamus (16–19). DTI based fiber tracking provides the opportunity to delineate defined anatomical structures in the vicinity of the Vim target in humans (11,18–21). Coenen et al. published two case reports in which he described excellent tremor reduction, when the active contact was located right inside the DRTT, defined by deterministic DTI fiber tracking (10,19). To the best of our knowledge this is the first study investigating the amount of tremor alleviation depending on the anatomic position of the stimulation site in relation to the dentato-rubrothalamic tract including more than one patient and more than one trajectory tested. The main questions of our investigations were:
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1. Is the DRTT the right target structure for tremor alleviation? 2. Can the DRTT be depicted reliably by fibertracking software based on the DTI sequences used in a routine setup?
If the DRTT is the right target structure, why did we find good tremor alleviation not only at stimulation sites inside the DRTT but also in locations posterior, inferior and lateral to the DRTT? And why could we not demonstrate that contacts further from the DRTT in a given direction have monotonically declining efficacy? There are two possible answers. We either did not depict the DRTT correctly or our stereotactic device and the transfer of the locations of intraoperative stimulation sites to the preoperative image data set was not accurate enough. DTI was performed with 12 read-out directions and relatively large voxel sizes on a 1.5 Tesla scanner. Modern DTI sequences use 32 or even 64 directions. Potentially, a higher number of readout directions, higher MRI field strengths and smaller voxel sizes could lead to more precise results (22). Additionally stereotactic CT scans with 1 mm slice thickness would further increase the resolution. Different tractography algorithms may lead to different results in the depiction of the chosen fiber tracts, as we have shown in a recent article (23). We performed “multi-step” deterministic tracking, thus, limiting the tracking results to match preconceived notions of the anatomy. Does that mean that deterministic tractography with our chosen regions of interest is just drawing lines we want to see on the image? We do not think so. Even with our standardized protocol we observed a significant variability in the course of the detected fiber tracts between left and right hemispheres and between different patients (15). The resolution of fibertracking is limited in areas of the brain where fibers of different functional tracts are getting in close contact or even cross each other. The DRTT takes course through areas of the brain stem and the diencephalon consisting of highly intermingled fiber tracts. Deterministic tracking algorithms follow the voxels with dominant fractional anisotropy, so it might well be that the tractography “jumps” from one tract to neighboring fibers which follow a different path as the originally chosen tract (24,25). In all of the 9 hemispheres, in which the DRTT could be depicted the fibers eventually merge with the pyramidal tract. Deterministic fiber tracking algorithms are based on the determination of the diffusion direction in one voxel according to the gaussian diffusion principle, which states that in one voxel only one set of fibers can be present (26– 30). In voxels with crossing, kissing or branching of fibers, the anisotropy is always low. To solve the problem of branching, modifications such as Euler’s method and the Runge-Kutta fourth-order algorithm has been developed, with the Runge-Kutta algorithm being the most precise (31). Deterministic algorithms are limited by the choice of initialization (32), sensitivity to the estimated principal direction, sophisticated computational statistics on tracts, and lack of connectivity information between regions of the brain (30). Deterministic fibertracking can be performed within minutes and therefore can be integrated in the preoperative planning for DBS procedures very conveniently. To solve the problem of branching, kissing or crossing fibers algorithms have been developed, like the mixture of tensors (30), higher rank tensor (33,34) ball-and-stick (35), Q-ball imaging algorithm (36,37) and diffusion spectrum imaging (38) They try to estimate how likely water molecules move in any particular direction at any particular speed. The main advantage of the probabilistic approach is that voxels with a low anisotropy in the path of a fiber can be bridged, and longer fiber pathways can be tracked and visualized (23). Probabilistic algorithms are computationally more elaborate than deterministic ones, but outperform them in dealing with partial volume averaging effects and noise in the estimated fiber directions. Most importantly, the output of probabilistic algorithms
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Figure 4. Afferents to the thalamus according to Hassler (29). Inferior-lateral aspect of the left thalamus. DRTT, dentato-rubro-thalamic tract; GPe, Globus pallidus externus; GPi, Globus pallidus internus; V.im, Nucl. ventralis intermedius; V.o.a, Nucl. ventrooralis anterior; V.o.p, Nucl. ventrooralis posterior; VA, Nucl. ventralis anterior; VPL, Nucl. ventralis posterolateralis.
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is usually designed to give a connectivity index measuring how likely two voxels are connected to one another (39). However, just as in deterministic fiber tracking, multiple parameters can be adjusted and there is no general agreement on which parameters should be chosen for which tract. To our knowledge, there is no study comparing probabilistic and deterministic fiber tracking algorithms for the DRTT. We have chosen to correlate the intraoperative stimulation sites with clinical effects, because we test multiple trajectories and along these at different insertion depths. Thereby we could investigate a larger area than by looking at the 4 contacts of the finally implanted electrode only. The accuracy of our stereotactic micro-drive is in the range of 1 mm. Prior to each stereotactic procedure we check the accuracy of the system with the phantom of our stereotactic device. However, the determination of the position of the FHC test electrode and its translation to the stereotactic space is problematic due to possible deviations of the trajectories of the microelectrodes in the brain and to fusion errors of different image data sets. We performed a postoperative CT scan, fused it to the preoperative MRI data set and compared the trajectory and insertion depth of the implanted electrode with the corresponding planned trajectory. Deviations lie in the range of 1.5 mm, which might explain why we could not find correlations between the distance of the stimulation site to the DRTT and tremor alleviation, (mean distance: 1.9 mm ± 1.6 mm) provided that we depicted the DRTT correctly. The clinical effects of each contact of the final DBS-electrode over time were not investigated in this study. Electric field sizes and forms could not be estimated, since the impedance values were not documented, intraoperatively (40). So, we have to rely on the position of the contact and the amplitude of current only. In a recently published paper by Sweet et al. no signifiwww.neuromodulationjournal.com
cant relationship was observed between the outcome and the position of the active contact relative to the DRTT in patients with Parkinson’s disease (41). However, they found a nonsignificant trend toward better outcome when the estimated volume of activation was closer to the DRTT. Due to the limited number of patients and sites in our own study the power of the statistical tests was below the desired value, so our negative results need to be interpreted cautiously. Assuming the DRTT we depicted is correct, how could we interpret the clinical effects depending on the position of the stimulation site relative to the DRTT? We found that stimulation sites located inside the DRTT or lateral to it provided better tremor alleviation than targets medial to the DRTT. We assume that more medial targets correspond to the internal (medial) part of the Vim representing the region of the head according to Hassler (4). Since all of our five patients suffered from hand tremor predominantly, more lateral stimulation sites achieved better clinical results due to stimulation in the external (lateral) part of the Vim representing the leg and arm region. On the other hand, stimulation sites positioned more laterally are prone to co-influence the pyramidal tract, leading to capsular effects. These side effects were not evaluated in this study, because we focused on the alleviation of tremor and the DRTT, solely. Stimulation sites inside or posterior to the DRTT reduced tremor significantly better than stimulations anterior to the DRTT. Therefore we conclude that stimulation of fibers running to the Vim or to the posterior part of the Nucleus ventralis oralis posterior [Vop, according to Hassler (42)] provide the best results. The fibers of the DRTT enter the thalamus in the Vop. Immediately posterior to the Vop anterior fibers of the lemniscus medialis with afferent tracts from muscle spindles enter the thalamus where the Vim is located (Fig. 4). More posteriorly positioned stimulation sites might cause
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THE DRTT IN ET-DBS paresthesias from medial lemniscus co-activation, if not ataxia (43), but here we exclusively focused on the alleviation of tremor and the DRTT and did not evaluate side effects and other tracts in this report. We obtained significantly better tremor alleviation at stimulation sites inside and inferior to the DRTT compared to stimulation sites superior to it. Therefore, the best stimulation site seems to be located at the inferior border of the Vim or even inferior to this subnucleus. These results are in accordance with the findings of Herzog et al. who found that high-frequency stimulation of the subthalamic area is more effective in alleviating postural and intention tremor than stimulation of the ventro-intermediate thalamic nucleus (44). The region just below the thalamus is very complex. The zona incerta is located here, surrounded by afferents to the thalamus from spinal, cerebellar and mesencephalic fiber tracts, as well as interconnections between the basal ganglia and the thalamus like the ansa lenticularis and the lenticular fascicle. Current literature does not provide enough evidence to attribute the specific effect of DBS on tremor to one of these fiber tracts. Finally, the DRTT is not a continuous tract of nerve fibers with very long axons like the medial lemniscus or the pyramidal tract. It is rather a chain of neurons artificially unmasked by fiber tracking due to the selected regions of interest. However, the DRTT has been described as a functional unit connecting the cerebellum to the thalamus and our DTI based course of it is in accordance with the reported anatomy (10,11). However, if the DRTT is not the right target, our negative findings concerning the lack of correlation between the distance of the stimulation site to the DRTT and tremor alleviation are well explained and one needs to look at other fiber tracts or anatomical structures that can be visualized in state-of-the art imaging. Comparisons of DTI protocols or tractography algorithms evaluating the delineation of a certain fiber tract/the DRTT in the living brain do not exist. In this study we evaluated the hard- and software we routinely use in the preparation and postoperative control of DBS procedures. The results do not provide sufficient evidence to define the DRTT as visualized by the chosen methods as a new target for tremor-DBS. Further investigations on different DTI sequences and fiber tracking algorithms are mandatory. It should be helpful to investigate and include additional fiber tracts into the data set to define the optimal stimulation site more precisely.
CONCLUSION We found significant differences in the extent of tremor alleviation depending on the position of intraoperative stimulation sites relative to the dentato-rubro-thalamic tract. With better results inside, posterior, lateral and inferior to the DRTT. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences and fiber tracking algorithms are mandatory.
Authorship Statements
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How to Cite this Article: Schlaier J., Anthofer J., Steib K., Fellner C., Rothenfusser E., Brawanski A., Lange M. 2015. Deep Brain Stimulation for EssentialTremor:Targeting the Dentato-Rubro-Thalamic Tract? Neuromodulation 2015; 18: 105–112
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Dr. Schlaier designed and conducted the study, including data collection, and data analysis. Drs. Anthofer and Steib conducted the study, including data collection, and data analysis. Dr. Lange designed and conducted the study, including data analysis. Drs.
Schlaier and Lange prepared the manuscript draft with important intellectual input from Drs. Fellner, Rothenfusser and Brawanski. All authors approved the final manuscript. All authors had complete access to the study data.
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Revised: July 8, 2014
Accepted: July 24, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12238
Deep Brain Stimulation for Essential Tremor: Targeting the Dentato-Rubro-Thalamic Tract? Juergen Schlaier, PhD*; Judith Anthofer, MD*; Kathrin Steib, MD*; Claudia Fellner, MD†; Eva Rothenfusser, MD‡; Alexander Brawanski, PhD*; Max Lange, MD* Objective: The aim of our study was to evaluate the influence of the stimulation site relative to the dentato-rubro-thalamic tract (DRTT) on the alleviation of tremor in deep brain stimulation. Methods: Ten DRTTs in five patients were investigated using preoperative diffusion tensor imaging (DTI). Regions of interest for fiber tracking were located in the cerebellar dentate nucleus, the superior cerebellar peduncle and the contralateral red nucleus. The position and distance of all intraoperative stimulation sites to the DRTT were measured and correlated to the amount of tremor reduction. Results: Nine of 10 DRTTs could be identified using DTI-based fiber tracking. Better tremor reduction was achieved in locations in or posterior and lateral to the DRTT than in medial and anterior positions (p = 0.001). Stimulation sites inferior to and in the DRTT achieved better results than locations superior to the DRTT (p < 0.05). The vicinity of the stimulation site to the DRTT did not correlate with tremor alleviation. Discussion: In deep brain stimulation targeting for thalamic stimulation sites is limited to statistical, atlas-based coordinates. Diffusion tensor imaging and fiber tracking was used to visualize the dentato-rubro-thalamic tract as a potential, individualized target structure. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. DTI sequences with a higher number of read-out directions, probabilistic fiber tracking and three Tesla MRI scanners may lead to different results in the depiction of the chosen fiber tract and may provide a better correlation with stimulation effects. Conclusions: The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences, and fiber tracking algorithms are mandatory. Keywords: DBS, DRTT, DTI, electrode placement, essential tremor, MRI, VIM Conflict of Interest: Dr. Schlaier has received teaching honoraria from Medtronic, Inc. and research support from the following companies: St. Jude Medical, Antisense Pharma and Medtronic. He gave several talks in the last several years, which were partly sponsored by Medtronic, St. Jude Medical, or BrainLab. He also serves as a consultant to Medtronic, Inc. and receives compensation for these services. Dr. Anthofer has received travel grants and training fees for educational courses in functional neurosurgery from Medtronic. Dr. Steib has received travel grants and training fees for educational courses in functional neurosurgery from Medtronic and St. Jude Medical. Dr. Fellner reports no conflict of interest. Dr. Rothenfusser received fees for serving as a speaker in courses sponsored by Ipsen and Merz. Dr. Brawanski reports no conflict of interest. Dr. Lange has received fees for serving as a speaker, a consultant, and an advisory board member for Medtronic and UCB, and he has received research funding from UCB and St. Jude Medical.
INTRODUCTION
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Address correspondence to: Max Lange, MD, Neurosurgery, University of Regensburg, Medical Center, Franz-Josef-Strauss-Allee 11, 93049 Regensburg, Germany. Email: [email protected] * Department of Neurosurgery, Medical Center, University of Regensburg, Regensburg, Germany; † Institute of Radiology, Medical Center, University of Regensburg, Regensburg, Germany; and ‡ Department of Neurology, Medical Center, University of Regensburg, Regensburg, Germany For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Financial support: The authors received no financial support for the study.
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Deep brain stimulation has become a well-established treatment option for patients suffering from essential tremor (1,2). Most centers focus on the nucleus ventralis intermedius (Vim) as the target of choice for planning the trajectory of the electrodes (3,4). On conventional MR sequences it is impossible to discriminate the Vim from the neighboring subnuclei of the thalamus. Therefore, the majority of neurosurgeons relies on probabilistic coordinates, derived from investigations of a limited number of postmortem human brains. As has been shown by several groups, the inter-individual, anatomical variability of target regions in deep brain stimulation is quite considerable, so the reliability of atlasbased coordinates may be insufficient (5–8). Spiegelmann et al., as well as Vassal et al., suggested special MR sequences on three
SCHLAIER ET AL. Tesla or 1.5 Tesla scanners to visualize the Vim directly on the images that are used for planning (1,9). Fiber tracking based on diffusion tensor imaging seems to represent another possibility to determine the target region. As suggested by Coenen et al. the visualization of the dentato-robro-thalamic tract (DRTT) might help to individualize targeting in patients with essential tremor (10). The aim of this study was to evaluate the amount of tremor reduction depending on the electrode position relative to the DRTT.
Table 1. MRI-Parameters. T2 sagittal
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T2 axial
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T1 sagittal mp-rage
MATERIAL AND METHODS
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In this retrospective, clinical study we included 5 patients (2 female, 3 male) with essential tremor, who consecutively underwent bilateral VIM-stimulation. Patient age ranged from 53–73 years (mean: 61.4 years). The duration of the disease from the first diagnosis to the operation ranged from 2 to 27 years (mean: 12.4 years).
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DTI
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Inclusion Criteria for DBS Patients with essential tremor and pronounced tremor-related functional disability in daily life despite optimal medical treatment were included. Exclusion Criteria for DBS Exclusion criteria were age >75 years, dementia, severe frontal lobe disturbances, insufficient compliance, coagulopathies, immunosuppression and tremors other than essential tremor. If MR images showed pronounced cerebral atrophy and signs of severe cerebral macroangiopathy, patients were excluded as well. Preoperative Planning All MRI scans for target and trajectory planning were performed under general anaesthesia. In all patients the MRI scan (1.5 Tesla; Avanto, Siemens, Erlangen, Germany) was performed separately from the stereotactic CTscan (Sensation 16, Siemens, Erlangen, Germany; CRW, Radionics, Burlington, MA). MR imaging included T2 weighted sagittal images for the detection of the anterior (AC) and posterior commissure (PC), T2 weighted axial images for the detection of the Vim target according to AC-PCrelated coordinates (see below), volumetric T1-weighted MRI, mp-rage for trajectory planning and diffusion tensor imaging (DTI) for fiber tracking of the DRTT (Table 1). CT imaging was performed with 2-mm slice thickness reaching from the foramen magnum to the vertex without gantry tilt. All acquired images were transferred to a computer workstation where all data sets were fused to the volumetric T1-weighted MRI (iPlan Stereotaxy 3.0, BrainLab, Feldkirchen, Germany). The coordinates of the anterior (AC) and posterior commissure (PC) were determined on the sagittal T2-weighted images and checked for accuracy on the volumetric T1-weighted slices.
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Fibertracking Deterministic fibertracking was performed using iPlan stereotaxy software (Brainlab, Feldkirchen, Germany). The Dentato-RubroThalamic Tract was obtained by selection of fibers passing through three regions of interest as suggested by Kwon and his colleagues 2011 (11) (Fig. 1a–c): www.neuromodulationjournal.com
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TR 3030 msec, TE 120 msec, turbo spin echo (tse) voxel size 0.9 mm × 0.7 mm × 2 mm distance factor 0.2 mm acquisition time, 3:43 min TR 4070 msec, TE 80 msec, spin echo (se) voxel size 1 mm × 1 mm × 2 mm no distance factor parallel to the intercommissural plane acquisition time 34:49 min double dose (0.2 mmol/kg bodyweight) Gadobutrol voxel size 0.9 mm × 0.9 mm × 1.1 mm slice orientation sagittal TR 1680 msec, TE 2970 msec, α (flip angle) 15° matrix 256 × 256, FOV 240 mm acquisition time, 7:55 min spin-echo echo-planar imaging pulse sequence number of gradient directions 12 3 mm slice thickness; 39 slices TR 5700 msec, TE 98 msec, PAT2 field of view, 230 mm matrix, 128 × 128 b value, 1000 sec/mm2 acquisition time, 4:01 min
• the dentate nucleus cerebelli contralateral to the VIM of interest • the superior cerebellar peduncle contralateral to the VIM of interest • and the ipsilateral red nucleus Minimal fiber length was set to 30 mm and we worked with a fractional anisotropy level of 0.15.
Atlas-Based Targeting Atlas-based targeting of the VIM was performed according to the suggestions of Osenbach and Burchiel (12): • ant/post: 25% of the intercommisural line (IC) anterior to the posterior commisure (PC) • laterality: 13–15 mm lateral to IC ○ (11 mm lateral to lateral wall of III. ventricle, if width of III. ventricle > 6 mm) • sup/inf: same axial slice as IC The trajectories of the electrodes were planned on volumetric T1-weighted MPRage contrast-enhanced images and controlled on CT slices after fusion. Four additional trajectories (anterior, posterior, lateral and medial) were planned at 2 mm distance to the center trajectory to simulate the path of the five possible electrodes, according to the configuration of the “ben-gun” manual microdrive (Medtronic, Minneapolis, MN). In all cases a frontal burr hole close to the coronal suture was planned. All trajectories had to avoid sulci, ventricles and white matter blood vessels. Trajectories were rejected, if they came too close ( 0.05).
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THE DRTT IN ET-DBS
Table 2. Positions of the Stimulation Sites Relative to the DRTT and the Corresponding Extent of Tremor Alleviation. Position
N
Extent of tremor alleviation (%) Mean Standard deviation
Inside DRTT Anterior Posterior Medial Lateral Inferior to the horizontal segment Superior to the horizontal segment
8 18 19 4 9 23 15
81.25 61.67 83.90 25.00 85.56 83.70 48.33
11.57 29.85 25.23 35.36 24.17 23.07 27.50
We further investigated the extent of tremor reduction dependent on the distance to the DRTT at 1 mA, 2 mA and 3 mA amplitudes of current. Again, we did not find statistical significant correlations for any of the amplitudes of current. By looking only at the stimulation sites located posterior to the DRTT we did not find better tremor alleviation in positions closer to that tract than in remote positions (p = 0.526, ANOVA on ranks). The same held true for all the other locations: anterior (p = 0.155), lateral (p = 0.531), medial (p = 0.141), inferior (p = 0.762) and superior (p = 0.645). In summary, better tremor reduction was achieved in locations directly inside the DRTT and in the quadrant posterior, inferior and lateral to it in comparison to anterior, medial and superior positions. The distance of the stimulation site to the nearest fiber of the DRTT had no influence on tremor alleviation.
DISCUSSION In deep brain stimulation for essential tremor the nucleus Vim is the target used most frequently (3). Targeting is mainly based on atlas-derived coordinates resulting from investigations of a limited number of brains of human corpses. It has been shown for the Vim and other targets that due to inter-individual, anatomical variations the atlas-based targeting is not perfect (5–8,15). Efforts have been undertaken to delineate the Vim directly on special MR sequences on 1.5 T and 3 T scanners (1,9). Other groups have used diffusion tensor imaging and fiber tracking to directly or indirectly visualize the target region in the ventro-lateral thalamus (16–19). DTI based fiber tracking provides the opportunity to delineate defined anatomical structures in the vicinity of the Vim target in humans (11,18–21). Coenen et al. published two case reports in which he described excellent tremor reduction, when the active contact was located right inside the DRTT, defined by deterministic DTI fiber tracking (10,19). To the best of our knowledge this is the first study investigating the amount of tremor alleviation depending on the anatomic position of the stimulation site in relation to the dentato-rubrothalamic tract including more than one patient and more than one trajectory tested. The main questions of our investigations were:
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1. Is the DRTT the right target structure for tremor alleviation? 2. Can the DRTT be depicted reliably by fibertracking software based on the DTI sequences used in a routine setup?
If the DRTT is the right target structure, why did we find good tremor alleviation not only at stimulation sites inside the DRTT but also in locations posterior, inferior and lateral to the DRTT? And why could we not demonstrate that contacts further from the DRTT in a given direction have monotonically declining efficacy? There are two possible answers. We either did not depict the DRTT correctly or our stereotactic device and the transfer of the locations of intraoperative stimulation sites to the preoperative image data set was not accurate enough. DTI was performed with 12 read-out directions and relatively large voxel sizes on a 1.5 Tesla scanner. Modern DTI sequences use 32 or even 64 directions. Potentially, a higher number of readout directions, higher MRI field strengths and smaller voxel sizes could lead to more precise results (22). Additionally stereotactic CT scans with 1 mm slice thickness would further increase the resolution. Different tractography algorithms may lead to different results in the depiction of the chosen fiber tracts, as we have shown in a recent article (23). We performed “multi-step” deterministic tracking, thus, limiting the tracking results to match preconceived notions of the anatomy. Does that mean that deterministic tractography with our chosen regions of interest is just drawing lines we want to see on the image? We do not think so. Even with our standardized protocol we observed a significant variability in the course of the detected fiber tracts between left and right hemispheres and between different patients (15). The resolution of fibertracking is limited in areas of the brain where fibers of different functional tracts are getting in close contact or even cross each other. The DRTT takes course through areas of the brain stem and the diencephalon consisting of highly intermingled fiber tracts. Deterministic tracking algorithms follow the voxels with dominant fractional anisotropy, so it might well be that the tractography “jumps” from one tract to neighboring fibers which follow a different path as the originally chosen tract (24,25). In all of the 9 hemispheres, in which the DRTT could be depicted the fibers eventually merge with the pyramidal tract. Deterministic fiber tracking algorithms are based on the determination of the diffusion direction in one voxel according to the gaussian diffusion principle, which states that in one voxel only one set of fibers can be present (26– 30). In voxels with crossing, kissing or branching of fibers, the anisotropy is always low. To solve the problem of branching, modifications such as Euler’s method and the Runge-Kutta fourth-order algorithm has been developed, with the Runge-Kutta algorithm being the most precise (31). Deterministic algorithms are limited by the choice of initialization (32), sensitivity to the estimated principal direction, sophisticated computational statistics on tracts, and lack of connectivity information between regions of the brain (30). Deterministic fibertracking can be performed within minutes and therefore can be integrated in the preoperative planning for DBS procedures very conveniently. To solve the problem of branching, kissing or crossing fibers algorithms have been developed, like the mixture of tensors (30), higher rank tensor (33,34) ball-and-stick (35), Q-ball imaging algorithm (36,37) and diffusion spectrum imaging (38) They try to estimate how likely water molecules move in any particular direction at any particular speed. The main advantage of the probabilistic approach is that voxels with a low anisotropy in the path of a fiber can be bridged, and longer fiber pathways can be tracked and visualized (23). Probabilistic algorithms are computationally more elaborate than deterministic ones, but outperform them in dealing with partial volume averaging effects and noise in the estimated fiber directions. Most importantly, the output of probabilistic algorithms
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Figure 4. Afferents to the thalamus according to Hassler (29). Inferior-lateral aspect of the left thalamus. DRTT, dentato-rubro-thalamic tract; GPe, Globus pallidus externus; GPi, Globus pallidus internus; V.im, Nucl. ventralis intermedius; V.o.a, Nucl. ventrooralis anterior; V.o.p, Nucl. ventrooralis posterior; VA, Nucl. ventralis anterior; VPL, Nucl. ventralis posterolateralis.
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is usually designed to give a connectivity index measuring how likely two voxels are connected to one another (39). However, just as in deterministic fiber tracking, multiple parameters can be adjusted and there is no general agreement on which parameters should be chosen for which tract. To our knowledge, there is no study comparing probabilistic and deterministic fiber tracking algorithms for the DRTT. We have chosen to correlate the intraoperative stimulation sites with clinical effects, because we test multiple trajectories and along these at different insertion depths. Thereby we could investigate a larger area than by looking at the 4 contacts of the finally implanted electrode only. The accuracy of our stereotactic micro-drive is in the range of 1 mm. Prior to each stereotactic procedure we check the accuracy of the system with the phantom of our stereotactic device. However, the determination of the position of the FHC test electrode and its translation to the stereotactic space is problematic due to possible deviations of the trajectories of the microelectrodes in the brain and to fusion errors of different image data sets. We performed a postoperative CT scan, fused it to the preoperative MRI data set and compared the trajectory and insertion depth of the implanted electrode with the corresponding planned trajectory. Deviations lie in the range of 1.5 mm, which might explain why we could not find correlations between the distance of the stimulation site to the DRTT and tremor alleviation, (mean distance: 1.9 mm ± 1.6 mm) provided that we depicted the DRTT correctly. The clinical effects of each contact of the final DBS-electrode over time were not investigated in this study. Electric field sizes and forms could not be estimated, since the impedance values were not documented, intraoperatively (40). So, we have to rely on the position of the contact and the amplitude of current only. In a recently published paper by Sweet et al. no signifiwww.neuromodulationjournal.com
cant relationship was observed between the outcome and the position of the active contact relative to the DRTT in patients with Parkinson’s disease (41). However, they found a nonsignificant trend toward better outcome when the estimated volume of activation was closer to the DRTT. Due to the limited number of patients and sites in our own study the power of the statistical tests was below the desired value, so our negative results need to be interpreted cautiously. Assuming the DRTT we depicted is correct, how could we interpret the clinical effects depending on the position of the stimulation site relative to the DRTT? We found that stimulation sites located inside the DRTT or lateral to it provided better tremor alleviation than targets medial to the DRTT. We assume that more medial targets correspond to the internal (medial) part of the Vim representing the region of the head according to Hassler (4). Since all of our five patients suffered from hand tremor predominantly, more lateral stimulation sites achieved better clinical results due to stimulation in the external (lateral) part of the Vim representing the leg and arm region. On the other hand, stimulation sites positioned more laterally are prone to co-influence the pyramidal tract, leading to capsular effects. These side effects were not evaluated in this study, because we focused on the alleviation of tremor and the DRTT, solely. Stimulation sites inside or posterior to the DRTT reduced tremor significantly better than stimulations anterior to the DRTT. Therefore we conclude that stimulation of fibers running to the Vim or to the posterior part of the Nucleus ventralis oralis posterior [Vop, according to Hassler (42)] provide the best results. The fibers of the DRTT enter the thalamus in the Vop. Immediately posterior to the Vop anterior fibers of the lemniscus medialis with afferent tracts from muscle spindles enter the thalamus where the Vim is located (Fig. 4). More posteriorly positioned stimulation sites might cause
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THE DRTT IN ET-DBS paresthesias from medial lemniscus co-activation, if not ataxia (43), but here we exclusively focused on the alleviation of tremor and the DRTT and did not evaluate side effects and other tracts in this report. We obtained significantly better tremor alleviation at stimulation sites inside and inferior to the DRTT compared to stimulation sites superior to it. Therefore, the best stimulation site seems to be located at the inferior border of the Vim or even inferior to this subnucleus. These results are in accordance with the findings of Herzog et al. who found that high-frequency stimulation of the subthalamic area is more effective in alleviating postural and intention tremor than stimulation of the ventro-intermediate thalamic nucleus (44). The region just below the thalamus is very complex. The zona incerta is located here, surrounded by afferents to the thalamus from spinal, cerebellar and mesencephalic fiber tracts, as well as interconnections between the basal ganglia and the thalamus like the ansa lenticularis and the lenticular fascicle. Current literature does not provide enough evidence to attribute the specific effect of DBS on tremor to one of these fiber tracts. Finally, the DRTT is not a continuous tract of nerve fibers with very long axons like the medial lemniscus or the pyramidal tract. It is rather a chain of neurons artificially unmasked by fiber tracking due to the selected regions of interest. However, the DRTT has been described as a functional unit connecting the cerebellum to the thalamus and our DTI based course of it is in accordance with the reported anatomy (10,11). However, if the DRTT is not the right target, our negative findings concerning the lack of correlation between the distance of the stimulation site to the DRTT and tremor alleviation are well explained and one needs to look at other fiber tracts or anatomical structures that can be visualized in state-of-the art imaging. Comparisons of DTI protocols or tractography algorithms evaluating the delineation of a certain fiber tract/the DRTT in the living brain do not exist. In this study we evaluated the hard- and software we routinely use in the preparation and postoperative control of DBS procedures. The results do not provide sufficient evidence to define the DRTT as visualized by the chosen methods as a new target for tremor-DBS. Further investigations on different DTI sequences and fiber tracking algorithms are mandatory. It should be helpful to investigate and include additional fiber tracts into the data set to define the optimal stimulation site more precisely.
CONCLUSION We found significant differences in the extent of tremor alleviation depending on the position of intraoperative stimulation sites relative to the dentato-rubro-thalamic tract. With better results inside, posterior, lateral and inferior to the DRTT. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences and fiber tracking algorithms are mandatory.
Authorship Statements
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How to Cite this Article: Schlaier J., Anthofer J., Steib K., Fellner C., Rothenfusser E., Brawanski A., Lange M. 2015. Deep Brain Stimulation for EssentialTremor:Targeting the Dentato-Rubro-Thalamic Tract? Neuromodulation 2015; 18: 105–112
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Dr. Schlaier designed and conducted the study, including data collection, and data analysis. Drs. Anthofer and Steib conducted the study, including data collection, and data analysis. Dr. Lange designed and conducted the study, including data analysis. Drs.
Schlaier and Lange prepared the manuscript draft with important intellectual input from Drs. Fellner, Rothenfusser and Brawanski. All authors approved the final manuscript. All authors had complete access to the study data.
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