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International audience; Group analysis consists of using an anatomical space as reference, transferring data such as contact location and extend of stimulation from each patient and relating them to the symptomatic effect. Analyzing past implantations should support understanding the mechanisms of action of DBS and predicting outcome in new patients. Most studies place their focus on the chronic stimulation situation, with the lead at a fixed position in the brain. This results in few data samples per patient, requiring large cohorts. On the other hand, intra-operative tests are an attractive source of data. The aim of this study was to develop a fully automated pipeline for analyzing the results of intra-operative stimulation tests of ventro-intermediate nucleus of the thalamus (Vim) for ET using high-fidelity data and exemplify the pipeline on a group of patients. Data from 19 DBS patients (6 ET, 16 PD) from the University Hospital Clermont-Ferrand (France) was used to create an MR template including patient-specific labels, resulting in a probabilistic definition of 57 deep brain structures. Data from the 6 ET patients in the group was used to create a probabilistic stimulation map (PSM). Tremor reduction was assessed during intra-operative stimulation tests using a wrist-worn acceleration sensor. These scores were combined with patient-specific electric field (EF) simulations into a 4D volume. The latter was first summarized into a weighted mean map (average of the improvement weighted by the EF norm). Voxels with low occurrence of fields (10% of max) and number of patients (2 of 6) were excluded. Secondly, the significance of the relationship between tremor reduction and electric field was estimated with Linear mixed models using patient as a random effect. Voxels in the weighted mean map with |p|>0.05 were excluded. A fully automated, reproducible workflow was established to normalize and analyze intra-operative data and allowed to identify regions with significant relationship between electric field and tremor suppression. In the future more patients will be integrated to conduct statistical verification of the identified regions.

International audience; The study describes a method to set up disease specific deep brain stimulation (DBS) atlases based on intra-operative stimulation test data exemplified with data from 6 essential tremor (ET) patients implanted in the ventrointermediate nucleus of the thalamus (Vim).I. INTRODUCTION DBS consists in delivering electric stimulation to the brain structures responsible for movement regulation using multi-contact electrodes in order to control symptoms of movement disorders. To ensure proper placement of the electrode during surgery, awake intra-operative testing of symptoms is common. Normative analysis methods have been applied by other groups [1] to study the mechanisms of action of DBS, but focus on stimulation settings and longterm symptoms and rarely study ET. In comparison, intra-operative tests during awake surgery produce a large amount of exploration data. We present in this paper the group analysis of intra-operative stimulation test data in patients who received DBS for ET.II. METHOD A group specific anatomical template was created based on WAIR (white matter attenuated inversion recovery) and T1 MR (magnetic resonance) images from 19 bilaterally implanted DBS patients (PD:13, ET:6). Deep brain structures manually delineated by the neurosurgeon were projected to and summarized in the template. The distribution of the electric field (EF) was resolved for the ET patients for each position and amplitude evaluated during surgery. In each voxel, tremor improvement and EF norm were used to discriminate voxels with scores significantly above or below average using one-sampled two-sided t-test.III. RESULTS The stimulation atlas describes the efficacy of DBS by combining the probabilistic anatomical template, outlines of deep brain structures and improvement scores. IVoxels associated for improvement above average concentrate in the Posterior subthalamic area (infero-posterior to Vim) extending in the direction of Zi and along the posterior limit of Vim. Voxels significant for improvement below average concentrate in the anterior and posterior limits of the region of interest.IV. DISCUSSION This study underlines the potential of the high quality data collected during surgery for the analysis of the mechanisms of action of DBS in tremor using state-of-the art group-analysis approaches. The low number of patients is compensated by the high number of tests in each patient, allowing to identify significant improvement regions. The next steps are the integration of more patients and investigation in different statistics approaches to capture and quantify reliability of the results.

International audience

International audience; Electrical stimulation of the deep parts of the brain is the standard answer for patients subject to drug-refractory movement disorders. Collective analysis of data collected during surgeries are crucial in order to provide more systematic planning assistance and understanding the physiological mechanisms of action. To that end, the process of normalizing anatomies captured with Magnetic Resonance imaging across patients is a key component. In this work, we present the optimization of a workflow designed to create group-specific anatomical templates: a group template is refined iteratively using the results of successive non-linear image registrations with refinement steps in the in the basal-ganglia area. All non-linear registrations were executed using the Advanced Normalization Tools (ANTs) and the quality of the nor-malization was measured using spacial overlap of anatomical structures manually delineated during the planning of the surgery. The parameters of the workflow evaluated were: the use of multiple modalities sequentially or together during each registration to the template, the number of iterations in the template creation and the fine settings of the non-linear registration tool. Using the T1 and white matter attenuated inverse recovery modalities (WAIR) together produced the best results, especially in the center of the brain. The optimal numbers of iterations of the template creation were higher than those from the literature and our previous works. Finally, the setting of the non-linear registration tool that improved results the most was the activation of the registration with the native voxel sizes of images, as opposed to down-sampled version of the images. The normalization process was optimized over our previous study and allowed to obtain the best possible anatomical nor-malization of this specific group of patient. It will be used to summarize and analyze peri-operative measurements during test stimulation. The aim is that the conclusions obtained from this analysis will be useful for assistance during the planning of new surgeries.

Highlights: • Non-linear iterative structural normalization method focused on the deep brain. • Multi-modality image data from deep brain stimulation patients. • Comparison of ANTS, FNIRT and DRAMMS for the non-linear registrations using different settings for each. • Evaluation of the registration tools based on the analysis of 58 structures of the deep brain segmented manually by a single expert. • ANTS was identified as the best performing non-linear registration tool., Deep brain stimulation (DBS) therapy requires extensive patient-specific planning prior to implantation to achieve optimal clinical outcomes. Collective analysis of patient’s brain images is promising in order to provide more systematic planning assistance. In this paper the design of a normalization pipeline using a group specific multi-modality iterative template creation process is presented. The focus was to compare the performance of a selection of freely available registration tools and select the best combination. The workflow was applied on 19 DBS patients with T1 and WAIR modality images available. Non-linear registrations were computed with ANTS, FNIRT and DRAMMS, using several settings from the literature. Registration accuracy was measured using single-expert labels of thalamic and subthalamic structures and their agreement across the group. The best performance was provided by ANTS using the High Variance settings published elsewhere. Neither FNIRT nor DRAMMS reached the level of performance of ANTS. The resulting normalized definition of anatomical structures were used to propose an atlas of the diencephalon region defining 58 structures using data from 19 patients.

Deep brain stimulation (DBS) is an established therapy for movement disorders such as essential tremor (ET). Positioning of the DBS lead in the patients brain is crucial for effective treatment. Extensive evaluations of improvement and adverse effects of stimulation at different positions for various current amplitudes are performed intraoperatively. However, to choose the optimal position of the lead, the information has to be "mentally" visualized and analyzed. This paper introduces a new technique called "stimulation maps," which summarizes and visualizes the high amount of relevant data with the aim to assist in identifying the optimal DBS lead position. It combines three methods: outlines of the relevant anatomical structures, quantitative symptom evaluation, and patient-specific electric field simulations. Through this combination, each voxel in the stimulation region is assigned one value of symptom improvement, resulting in the division of stimulation region into areas with different improvement levels. This technique was applied retrospectively to five ET patients in the University Hospital in Clermont-Ferrand, France. Apart from identifying the optimal implant position, the resultant nine maps show that the highest improvement region is frequently in the posterior subthalamic area. The results demonstrate the utility of the stimulation maps in identifying the optimal implant position. Graphical abstract Funding Agencies|Swiss National Science FoundationSwiss National Science Foundation (SNSF) [CR3212_153370]; Germaine de Stael program of the Swiss Academy of Engineering Sciences; French Ministry of Health [2011-A00774-37]; Swedish Research CouncilSwedish Research Council [2016-03564]; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [BD15-0032]

International audience; Deep brain stimulation (DBS) represents today a well-established treatment for movement disorders. Nevertheless the exact mechanism of action of DBS remains incompletely known. During surgery, numerous stimulation tests are frequently performed in order to evaluate therapeutic and adverse effects before choosing the optimal implantation site for the DBS lead. Anatomical structures responsible for the induced adverse effects have been investigated previously, but only based on stimulation data obtained with the implanted DBS lead. The present study introduces a methodology to identify these anatomical structures during intraoperative stimulation tests based on patient-specific electric field simulations and visualization on the patient specific anatomy. The application to 4 patients undergoing DBS surgery and presenting dysarthria, paresthesia or pyramidal effects shows the different anatomical structures, which might be responsible for the adverse effects. Several of the identified structures have been previously described in the literature. To draw any statistically significant conclusions, the methodology has to be applied to further patients. Together with the visualization of the therapeutic effects, this new approach could assist the neurosurgeons in the future in choosing the optimal implant position.

International audience; Deep brain stimulation (DBS) is used for symptomatic treatment of movement disorders. In many centers, the optimal DBS position is identified by intra-operative stimulation tests, which are performed at several positions along the planned trajectories toward the target structure with various stimulation amplitudes. The aim of the study was to propose a methodology summarizing all available intra-operative data of different patients to an atlas to provide targeting guidelines in the thalamus.

International audience; Despite an increasing use of deep brain stimulation (DBS) the fundamental mechanisms of action remain largely unknown. Simulation of electric entities has previously been proposed for chronic DBS combined with subjective symptom evaluations, but not for intraoperative stimulation tests. The present paper introduces a method for an objective exploitation of intraoperative stimulation test data to identify the optimal implant position of the chronic DBS lead by relating the electric field (EF) simulations to the patient-specific anatomy and the clinical effects quantified by accelerometry. To illustrate the feasibility of this approach, it was applied to five patients with essential tremor bilaterally implanted in the ventral intermediate nucleus (VIM). The VIM and its neighborhood structures were preoperatively outlined in 3D on white matter attenuated inversion recovery MR images. Quantitative intraoperative clinical assessments were performed using accelerometry. EF simulations (n = 272) for intraoperative stimulation test data performed along two trajectories per side were setup using the finite element method for 143 stimulation test positions. The resulting EF isosurface of 0.2 V/mm was superimposed to the outlined anatomical structures. The percentage of volume of each structure's overlap was calculated and related to the corresponding clinical improvement. The proposed concept has been successfully applied to the five patients. For higher clinical improvements, not only the VIM but as well other neighboring structures were covered by the EF isosurfaces. The percentage of the volumes of the VIM, of the nucleus intermediate lateral of the thalamus and the prelemniscal radiations within the prerubral field of Forel increased for clinical improvements higher than 50% compared to improvements lower than 50%. The presented new concept allows a detailed and objective analysis of a high amount of intraoperative data to identify the optimal stimulation target. First results indicate agreement with published data hypothesizing that the stimulation of other structures than the VIM might be responsible for good clinical effects in essential tremor. (Clinical trial reference number: Ref: 2011-A00774-37/AU905)