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See detailFastField: An Open-Source Toolbox for Efficient Approximation of Deep Brain Stimulation Electric Fields
Baniasadi, Mehri UL; Proverbio, Daniele UL; Goncalves, Jorge UL et al

E-print/Working paper (2020)

Deep brain stimulation (DBS) is a surgical therapy to alleviate symptoms of certain brain disorders by electrically modulating neural tissues. Computational models predicting electric fields and volumes ... [more ▼]

Deep brain stimulation (DBS) is a surgical therapy to alleviate symptoms of certain brain disorders by electrically modulating neural tissues. Computational models predicting electric fields and volumes of tissue activated are key for efficient parameter tuning and network analysis. Currently, we lack efficient and flexible software implementations supporting complex electrode geometries and stimulation settings. Available tools are either too slow (e.g. finite element method–FEM), or too simple, with limited applicability to basic use-cases. This paper introduces FastField, an efficient open-source toolbox for DBS electric field and VTA approximations. It computes scalable e-field approximations based on the principle of superposition, and VTA activation models from pulse width and axon diameter. In benchmarks and case studies, FastField is solved in about 0.2s, ~ 1000 times faster than using FEM. Moreover, it is almost as accurate as using FEM: average Dice overlap of 92%, which is around typical noise levels found in clinical data. Hence, FastField has the potential to foster efficient optimization studies and to support clinical applications [less ▲]

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See detailFrom tech to bench: Deep Learning pipeline for image segmentation of high-throughput high-content microscopy data
Garcia Santa Cruz, Beatriz UL; Jarazo, Javier UL; Saraiva, Claudia UL et al

Poster (2019, November 29)

Automation of biological image analysis is essential to boost biomedical research. The study of complex diseases such as neurodegenerative diseases calls for big amounts of data to build models towards ... [more ▼]

Automation of biological image analysis is essential to boost biomedical research. The study of complex diseases such as neurodegenerative diseases calls for big amounts of data to build models towards precision medicine. Such data acquisition is feasible in the context of high-throughput screening in which the quality of the results relays on the accuracy of image analysis. Although the state-of-the-art solutions for image segmentation employ deep learning approaches, the high cost of manual data curation is hampering the real use in current biomedical research laboratories. Here, we propose a pipeline that employs deep learning not only to conduct accurate segmentation but also to assist with the creation of high-quality datasets in a less time-consuming solution for the experts. Weakly-labelled datasets are becoming a common alternative as a starting point to develop real-world solutions. Traditional approaches based on classical multimedia signal processing were employed to generate a pipeline specifically optimized for the high-throughput screening images of iPSC fused with rosella biosensor. Such pipeline produced good segmentation results but with several inaccuracies. We employed the weakly-labelled masks produced in this pipeline to train a multiclass semantic segmentation CNN solution based on U-net architecture. Since a strong class imbalance was detected between the classes, we employed a class sensitive cost function: Dice coe!cient. Next, we evaluated the accuracy between the weakly-labelled data and the trained network segmentation using double-blind tests conducted by experts in cell biology with experience in this type of images; as well as traditional metrics to evaluate the quality of the segmentation using manually curated segmentations by cell biology experts. In all the evaluations the prediction of the neural network overcomes the weakly-labelled data quality segmentation. Another big handicap that complicates the use of deep learning solutions in wet lab environments is the lack of user-friendly tools for non-computational experts such as biologists. To complete our solution, we integrated the trained network on a GUI built on MATLAB environment with non-programming requirements for the user. This integration allows conducting semantic segmentation of microscopy images in a few seconds. In addition, thanks to the patch-based approach it can be employed in images with different sizes. Finally, the human-experts can correct the potential inaccuracies of the prediction in a simple interactive way which can be easily stored and employed to re-train the network to improve its accuracy. In conclusion, our solution focuses on two important bottlenecks to translate leading-edge technologies in computer vision to biomedical research: On one hand, the effortless obtention of high-quality datasets with expertise supervision taking advantage of the proven ability of our CNN solution to generalize from weakly-labelled inaccuracies. On the other hand, the ease of use provided by the GUI integration of our solution to both segment images and interact with the predicted output. Overall this approach looks promising for fast adaptability to new scenarios. [less ▲]

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See detailDeep Learning Quality Control for High-Throughput High-Content Screening Microscopy Images
Garcia Santa Cruz, Beatriz UL; Jarazo, Javier UL; Schwamborn, Jens Christian UL et al

Poster (2019, October 10)

Automation of biological image analysis is essential to boost biomedical research. The study of complex diseases such as neurodegenerative diseases calls for big amounts of data to build models towards ... [more ▼]

Automation of biological image analysis is essential to boost biomedical research. The study of complex diseases such as neurodegenerative diseases calls for big amounts of data to build models towards precision medicine. Such data acquisition is feasible in the context of high-throughput high-content screening (HTHCS) in which the quality of the results relays on the accuracy of image analysis. Deep learning (DL) yields great performance in image analysis tasks especially with big amounts of data such as the produced in HTHCS contexts. Such DL and HTHCS strength is also their biggest weakness since DL solutions are highly sensitive to bad quality datasets. Hence, accurate Quality Control (QC) for microscopy HTHCS becomes an essential step to obtain reliable pipelines for HTHCS analysis. Usually, artifacts found on these platforms are the consequence of out-of-focus and undesirable density variations. The importance of accurate outlier detection becomes essential for both the training process of generic ML solutions (i.e. segmentation or classification) and the QC of the input data such solution will predict on. Moreover, during the QC of the input dataset, we aim not only to discard unsuitable images but to report the user on the quality of its dataset giving the user the choice to keep or discard the bad images. To build the QC solution we employed fluorescent microscopy images of rosella biosensor generated in the HTHCS platform. A total of 15 planes ranging from -6z to +7z steps to the two optimum planes. We evaluated 27 known focus measure operators and concluded that they have low sensitivity in noisy conditions. We propose a CNN solution which predicts the focus error based on the distance to the optimal plane, outperforming the evaluated focus operators. This QC allows for better results in cell segmentation models based on U-Net architecture as well as promising improvements in image classification tasks. [less ▲]

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See detailApproXON: Heuristic Approximation to the E-Field-Threshold for Deep Brain Stimulation Volume-of-Tissue-Activated Estimation
Proverbio, Daniele UL; Husch, Andreas UL

E-print/Working paper (2019)

This paper introduces a heuristic approximation of the e-field threshold used for volume-of-tissue activated computation in deep brain stimulation. Pulse width and axon diameter are used as predictors. An ... [more ▼]

This paper introduces a heuristic approximation of the e-field threshold used for volume-of-tissue activated computation in deep brain stimulation. Pulse width and axon diameter are used as predictors. An open source implementation in MATLAB is provided together with an integration in the open LeadDBS deep brain stimulation research toolbox. [less ▲]

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See detailPATH-29. POTENTIAL OF RAMAN SPECTROSCOPY IN ONCOLOGICAL NEUROSURGERY
Kleine Borgmann, Felix; Husch, Andreas UL; Slimani, Redouane et al

Poster (2019)

Raman spectroscopy (RS) has gained increasing interest for the analysis of biological tissues within the recent years. It is a label-free, non-destructive method providing insights in biochemical ... [more ▼]

Raman spectroscopy (RS) has gained increasing interest for the analysis of biological tissues within the recent years. It is a label-free, non-destructive method providing insights in biochemical properties of tumor cells. It is possible to compare RS signals with histological properties of identical tissue parts. Therefore, RS bears promising potentials in neurosurgical neurooncology. On one hand, it could potentially be used for both intraoperative tumor diagnostics and resection control. On the other hand, it could provide important knowledge on tumor biochemistry and used for a subclassification of tumors with a potential impact on personalized therapy approaches. Within our group, we analyzed over 3000 measurement points in different brain tumors ex vivo with a robotized RS system and correlated the spectral curves with histopathological results. We separated and subclassified the data by AI-based methods. Additionally, we compared the latter results with those of a handheld probe, which is potentially navigatable for in vivo, intraoperative applications. We could demonstrate, that it is possible to separate distinct tumor groups only based on RS signals, especially by using computer-based signal analysis. Furthermore, we could demonstrate the differences of the spectra of deep-frozen and formalin-fixed tissues versus non-fixed tissues. Based on our results, we will highlight the potentials of RS for intraoperative neurosurgical application in resection control for brain tumors, as well as we will focus on the potentials for brain tumor diagnostics based purely on this method or by using it as an adjunct. Those methods bear additional potentials in the field of personalized chemotherapy approaches. [less ▲]

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See detailHabenula deep brain stimulation for refractory bipolar disorder.
Zhang, Chencheng; Kim, Seung-Goo; Li, Dianyou et al

in Brain stimulation (2019)

Bipolar disorder (BD) is a mood disorder associated with significant morbidity and mortality. In many cases, BD can be managed with pharmacotherapy, psychological therapy, or electroconvulsive therapy [1 ... [more ▼]

Bipolar disorder (BD) is a mood disorder associated with significant morbidity and mortality. In many cases, BD can be managed with pharmacotherapy, psychological therapy, or electroconvulsive therapy [1]. For some afflicted patients, however, BD is a chronic and severely disabling condition that is resistant to the aforementioned treatments. Deep brain stimulation (DBS) offers a safe and effective neurosurgical treatment for otherwise refractory movement disorders and obsessive-compulsive disorder [2,3]. [less ▲]

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See detailLead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging.
Horn, Andreas; Li, Ningfei; Dembek, Till A. et al

in NeuroImage (2018)

Deep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment ... [more ▼]

Deep brain stimulation (DBS) is a highly efficacious treatment option for movement disorders and a growing number of other indications are investigated in clinical trials. To ensure optimal treatment outcome, exact electrode placement is required. Moreover, to analyze the relationship between electrode location and clinical results, a precise reconstruction of electrode placement is required, posing specific challenges to the field of neuroimaging. Since 2014 the open source toolbox Lead-DBS is available, which aims at facilitating this process. The tool has since become a popular platform for DBS imaging. With support of a broad community of researchers worldwide, methods have been continuously updated and complemented by new tools for tasks such as multispectral nonlinear registration, structural/functional connectivity analyses, brain shift correction, reconstruction of microelectrode recordings and orientation detection of segmented DBS leads. The rapid development and emergence of these methods in DBS data analysis require us to revisit and revise the pipelines introduced in the original methods publication. Here we demonstrate the updated DBS and connectome pipelines of Lead-DBS using a single patient example with state-of-the-art high-field imaging as well as a retrospective cohort of patients scanned in a typical clinical setting at 1.5T. Imaging data of the 3T example patient is co-registered using five algorithms and nonlinearly warped into template space using ten approaches for comparative purposes. After reconstruction of DBS electrodes (which is possible using three methods and a specific refinement tool), the volume of tissue activated is calculated for two DBS settings using four distinct models and various parameters. Finally, four whole-brain tractography algorithms are applied to the patient's preoperative diffusion MRI data and structural as well as functional connectivity between the stimulation volume and other brain areas are estimated using a total of eight approaches and datasets. In addition, we demonstrate impact of selected preprocessing strategies on the retrospective sample of 51 PD patients. We compare the amount of variance in clinical improvement that can be explained by the computer model depending on the method of choice. This work represents a multi-institutional collaborative effort to develop a comprehensive, open source pipeline for DBS imaging and connectomics, which has already empowered several studies, and may facilitate a variety of future studies in the field. [less ▲]

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See detailUsing automated electrode localization to guide stimulation management in DBS
Petersen, Mikkel V.; Husch, Andreas UL; Parsons, Christine E. et al

in Annals of Clinical and Translational Neurology (2018), 0(0),

Abstract Deep Brain Stimulation requires extensive postoperative testing of stimulation parameters to achieve optimal outcomes. Testing is typically not guided by neuroanatomical information on electrode ... [more ▼]

Abstract Deep Brain Stimulation requires extensive postoperative testing of stimulation parameters to achieve optimal outcomes. Testing is typically not guided by neuroanatomical information on electrode contact locations. To address this, we present an automated reconstruction of electrode locations relative to the treatment target, the subthalamic nucleus, comparing different targeting methods: atlas‐, manual‐, or tractography‐based subthalamic nucleus segmentation. We found that most electrode contacts chosen to deliver stimulation were closest or second closest to the atlas‐based subthalamic nucleus target. We suggest that information on each electrode contact's location, which can be obtained using atlas‐based methods, might guide clinicians during postoperative stimulation testing. [less ▲]

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See detailPost-operative deep brain stimulation assessment: Automatic data integration and report generation
Husch, Andreas UL; Petersen, Mikkel V.; Gemmar, Peter et al

in Brain Stimulation (2018)

Background The gold standard for post-operative deep brain stimulation (DBS) parameter tuning is a monopolar review of all stimulation contacts, a strategy being challenged by recent developments of more ... [more ▼]

Background The gold standard for post-operative deep brain stimulation (DBS) parameter tuning is a monopolar review of all stimulation contacts, a strategy being challenged by recent developments of more complex electrode leads. Objective Providing a method to guide clinicians on DBS assessment and parameter tuning by automatically integrating patient individual data. Methods We present a fully automatic method for visualization of individual deep brain structures in relation to a DBS lead by combining precise electrode recovery from post-operative imaging with individual estimates of deep brain morphology utilizing a 7T-MRI deep brain atlas. Results The method was evaluated on 20 STN DBS cases. It demonstrated robust automatic creation of 3D-enabled PDF reports visualizing electrode to brain structure relations and proved valuable in detecting miss placed electrodes. Discussion Automatic DBS assessment is feasible and can conveniently provide clinicians with relevant information on DBS contact positions in relation to important anatomical structures. [less ▲]

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See detailPaCER - A fully automated method for electrode trajectory and contact reconstruction in deep brain stimulation
Husch, Andreas UL; Petersen, Mikkel V.; Gemmar, Peter et al

in NeuroImage: Clinical (2018), 17

Abstract Deep brain stimulation (DBS) is a neurosurgical intervention where electrodes are permanently implanted into the brain in order to modulate pathologic neural activity. The post-operative ... [more ▼]

Abstract Deep brain stimulation (DBS) is a neurosurgical intervention where electrodes are permanently implanted into the brain in order to modulate pathologic neural activity. The post-operative reconstruction of the DBS electrodes is important for an efficient stimulation parameter tuning. A major limitation of existing approaches for electrode reconstruction from post-operative imaging that prevents the clinical routine use is that they are manual or semi-automatic, and thus both time-consuming and subjective. Moreover, the existing methods rely on a simplified model of a straight line electrode trajectory, rather than the more realistic curved trajectory. The main contribution of this paper is that for the first time we present a highly accurate and fully automated method for electrode reconstruction that considers curved trajectories. The robustness of our proposed method is demonstrated using a multi-center clinical dataset consisting of N=44 electrodes. In all cases the electrode trajectories were successfully identified and reconstructed. In addition, the accuracy is demonstrated quantitatively using a high-accuracy phantom with known ground truth. In the phantom experiment, the method could detect individual electrode contacts with high accuracy and the trajectory reconstruction reached an error level below 100 μm (0.046 ± 0.025 mm). An implementation of the method is made publicly available such that it can directly be used by researchers or clinicians. This constitutes an important step towards future integration of lead reconstruction into standard clinical care. [less ▲]

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See detailIntegration of sparse electrophysiological measurements with preoperative MRI using 3D surface estimation in deep brain stimulation surgery
Husch, Andreas UL; Gemmar, Peter; Thunberg, Johan UL et al

in Webster, Robert; Fei, Baowei (Eds.) Medical Imaging 2017: Image-Guided Procedures, Robotic Interventions, and Modeling (2017, February 14)

Intraoperative microelectrode recordings (MER) have been used for several decades to guide neurosurgeons during the implantation of Deep Brain Stimulation (DBS) electrodes, especially when targeting the ... [more ▼]

Intraoperative microelectrode recordings (MER) have been used for several decades to guide neurosurgeons during the implantation of Deep Brain Stimulation (DBS) electrodes, especially when targeting the subthalamic nucleus (STN) to suppress the symptoms of Parkinson’s Disease. The standard approach is to use an array of up to five MER electrodes in a fixed configuration. Interpretation of the recorded signals yields a spatiallyvery sparse set of information about the morphology of the respective brain structures in the targeted area. However, no aid is currently available for surgeons to intraoperatively integrate this information with other data available on the patient’s individual morphology (e.g. MR imaging data used for surgical planning). This integration might allow surgeons to better determine the most probable position of the electrodes within the target structure during surgery. This paper suggests a method for reconstructing a surface patch from the sparse MER dataset utilizing additional a-priori knowledge about the geometrical configuration of the measurement electrodes. The conventional representation of MER measurements as intervals of target region/non-target region is therefore transformed into an equivalent boundary set representation, allowing efficient point-based calculations. Subsequently, the problem is to integrate the resulting patch with a preoperative model of the target structure, which can be formulated as registration problem minimizing a distance measure between the two surfaces. When restricting this registration procedure to translations, which is reasonable given certain geometric considerations, the problem can be solved globally by employing an exhaustive search with arbitrary precision in polynomial time. The proposed method is demonstrated using bilateral STN/Substantia Nigra segmentation data from preoperative MRIs of 17 Patients with simulated MER electrode placement. When using simulated data of heavily perturbed electrodes and subsequent MER measuremen [less ▲]

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See detailFast Correspondences for Statistical Shape Models of Brain Structures
Bernard, Florian UL; Vlassis, Nikos UL; Gemmar, Peter et al

in SPIE Medical Imaging (2016, March)

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See detailA solution for Multi-Alignment by Transformation Synchronisation
Bernard, Florian UL; Thunberg, Johan UL; Gemmar, Peter et al

in The proceedings of the IEEE Conference on Computer Vision and Pattern Recognition (CVPR) (2015)

The alignment of a set of objects by means of transformations plays an important role in computer vision. Whilst the case for only two objects can be solved globally, when multiple objects are considered ... [more ▼]

The alignment of a set of objects by means of transformations plays an important role in computer vision. Whilst the case for only two objects can be solved globally, when multiple objects are considered usually iterative methods are used. In practice the iterative methods perform well if the relative transformations between any pair of objects are free of noise. However, if only noisy relative transformations are available (e.g. due to missing data or wrong correspondences) the iterative methods may fail. Based on the observation that the underlying noise-free transformations lie in the null space of a matrix that can directly be obtained from pairwise alignments, this paper presents a novel method for the synchronisation of pairwise transformations such that they are globally consistent. Simulations demonstrate that for a high amount of noise, a large proportion of missing data and even for wrong correspondence assignments the method delivers encouraging results. [less ▲]

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See detailAssessment of Electrode Displacement and Deformation with Respect to Pre-Operative Planning in Deep Brain Stimulation
Husch, Andreas UL; Gemmar, Peter; Lohscheller, Jörg et al

in Handels, Heinz; Deserno, Thomas Martin; Meinzer, Hans-Peter (Eds.) et al Bildverarbeitung für die Medizin 2015 (2015)

The post-operative validation of deep brain stimulation electrode displacement and deformation is an important task towards improved DBS targeting. In this paper a method is proposed to align models of ... [more ▼]

The post-operative validation of deep brain stimulation electrode displacement and deformation is an important task towards improved DBS targeting. In this paper a method is proposed to align models of deep brain stimulation electrodes that are automatically extracted from post-operative CT imaging in a common coordinate system utilizing the planning data as reference. This enables the assessment of electrode displacement and deformation over the whole length of the trajectory with respect to the pre-operative planning. Accordingly, it enables the estimation of plan deviations in the surgical process as well as cross-patient statistics on electrode deformation, e.g. the bending induced by brain-shift. [less ▲]

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See detailSusceptibility-Weighted MRI for Deep Brain Stimulation: Potentials in Trajectory Planning
Hertel, Frank UL; Husch, Andreas UL; Dooms, Georges et al

in Stereotactic & Functional Neurosurgery (2015), 93(5), 303-308

Background: Deep brain stimulation (DBS) trajectory plan- ning is mostly based on standard 3-D T1-weighted gado- linium-enhanced MRI sequences (T1-Gd). Susceptibility- weighted MRI sequences (SWI) show ... [more ▼]

Background: Deep brain stimulation (DBS) trajectory plan- ning is mostly based on standard 3-D T1-weighted gado- linium-enhanced MRI sequences (T1-Gd). Susceptibility- weighted MRI sequences (SWI) show neurovascular struc- tures without the use of contrast agents. The aim of this study was to investigate whether SWI might be useful in DBS trajectory planning. Methods: We performed bilateral DBS planning using conventional T1-Gd images of 10 patients with different kinds of movement disorders. Afterwards, we matched SWI sequences and compared the visibility of vas- cular structures in both imaging modalities. Results: By ana- lyzing 100 possible trajectories, we found a potential vascu- lar conflict in 13 trajectories based on T1-Gd in contrast to 53 in SWI. Remarkably, all vessels visible in T1-Gd were also de- picted in SWI, whereas SWI showed many additional vascular structures which could not be identified in T1-Gd. Conclu- sion/Discussion: The sensitivity for detecting neurovascular structures for DBS planning seems to be significantly higher in SWI. As SWI does not require a contrast agent, we suggest that SWI may be a valuable alternative to T1-Gd MRI for DBS trajectory planning. Furthermore, the data analysis suggests that vascular interactions of DBS trajectories might be more frequent than expected from the very low incidence of symptomatic bleedings. The explanation for this is currently the subject of debate and merits further studies. [less ▲]

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See detailTransitively Consistent and Unbiased Multi-Image Registration Using Numerically Stable Transformation Synchronisation
Bernard, Florian UL; Thunberg, Johan UL; Salamanca Mino, Luis UL et al

in MIDAS Journal (2015)

Abstract. Transitive consistency of pairwise transformations is a desir- able property of groupwise image registration procedures. The transfor- mation synchronisation method [4] is able to retrieve ... [more ▼]

Abstract. Transitive consistency of pairwise transformations is a desir- able property of groupwise image registration procedures. The transfor- mation synchronisation method [4] is able to retrieve transitively con- sistent pairwise transformations from pairwise transformations that are initially not transitively consistent. In the present paper, we present a numerically stable implementation of the transformation synchronisa- tion method for a ne transformations, which can deal with very large translations, such as those occurring in medical images where the coor- dinate origins may be far away from each other. By using this method in conjunction with any pairwise (a ne) image registration algorithm, a transitively consistent and unbiased groupwise image registration can be achieved. Experiments involving the average template generation from 3D brain images demonstrate that the method is more robust with re- spect to outliers and achieves higher registration accuracy compared to reference-based registration. [less ▲]

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See detailAn Extensible Development Environment for 3D Segmentations based on Active Shape Models
Bernard, Florian UL; Gemmar, Peter; Husch, Andreas UL et al

in Shape Symposium (2014)

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See detailDTI of the visual pathway - white matter tracts and cerebral lesions.
Hana, Ardian; Husch, Andreas UL; Gunness, Vimal Raj Nitish et al

in Journal of visualized experiments : JoVE (2014), (90),

DTI is a technique that identifies white matter tracts (WMT) non-invasively in healthy and non-healthy patients using diffusion measurements. Similar to visual pathways (VP), WMT are not visible with ... [more ▼]

DTI is a technique that identifies white matter tracts (WMT) non-invasively in healthy and non-healthy patients using diffusion measurements. Similar to visual pathways (VP), WMT are not visible with classical MRI or intra-operatively with microscope. DIT will help neurosurgeons to prevent destruction of the VP while removing lesions adjacent to this WMT. We have performed DTI on fifty patients before and after surgery between March 2012 to January 2014. To navigate we used a 3DT1-weighted sequence. Additionally, we performed a T2-weighted and DTI-sequences. The parameters used were, FOV: 200 x 200 mm, slice thickness: 2 mm, and acquisition matrix: 96 x 96 yielding nearly isotropic voxels of 2 x 2 x 2 mm. Axial MRI was carried out using a 32 gradient direction and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2 and b-value of 800 s/mm(2). The scanning time was less than 9 min. The DTI-data obtained were processed using a FDA approved surgical navigation system program which uses a straightforward fiber-tracking approach known as fiber assignment by continuous tracking (FACT). This is based on the propagation of lines between regions of interest (ROI) which is defined by a physician. A maximum angle of 50, FA start value of 0.10 and ADC stop value of 0.20 mm(2)/s were the parameters used for tractography. There are some limitations to this technique. The limited acquisition time frame enforces trade-offs in the image quality. Another important point not to be neglected is the brain shift during surgery. As for the latter intra-operative MRI might be helpful. Furthermore the risk of false positive or false negative tracts needs to be taken into account which might compromise the final results. [less ▲]

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See detailData Integration for Image Guided Deep Brain Stimulation
Husch, Andreas UL

Doctoral thesis (n.d.)

Detailed reference viewed: 90 (22 UL)