Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.

Author Correction: Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.

In this Letter, Dominic Grün and Sagar have been added to the author list (affiliated with Max-Planck-Institute of Immunology and Epigenetics (MPI-IE), Freiburg, Germany). The author list, 'Author contribution' and 'Acknowledgements' sections have been corrected online. See accompanying Amendment.

Patient-derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma.

AIMS: How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. METHODS: We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. RESULTS: We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. CONCLUSION: This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.

Usage of augmented reality for interventional neuraxial procedures: A phantom-based study.

BACKGROUND: Neuraxial access is necessary for an array of procedures in anaesthesia, interventional pain medicine and neurosurgery. The commonly used anatomical landmark technique is challenging and requires practical experience. OBJECTIVE: We aimed to evaluate the technical feasibility of an augmented reality-guided approach for neuraxial access and tested the hypothesis that its use would improve success as the primary outcome. As secondary outcomes, we measured accuracy and the procedural duration compared with the classical landmark approach. DESIGN: A randomised phantom-based study. SETTING: The three-dimensional image of a thoracolumbar phantom spine model with the surrounding soft tissue was created with a neurosurgical planning workstation and ideal trajectories to the epidural space on the levels T10-L1 were planned using a paramedian approach. Both the three-dimensional holographic image of the spine and the trajectories were transferred to an augmented reality-headset. Four probands (two anaesthesiologists, one neuroradiologist and one stereotactic neurosurgeon) performed 20 attempts, 10 each of either conventional landmark or augmented reality-guided epidural punctures, where anatomical level, side and sequence of modality were all randomised. OUTCOME MEASURES: Accuracy was assessed by measuring Euclidean distance and lateral deviation from the predefined target point. Success of epidural puncture on the first attempt was compared between the conventional and the augmented reality-guided approaches. RESULTS: Success was achieved in 82.5% of the attempts using augmented reality technique, compared with 40% with the conventional approach [ P  = 0.0002, odds ratio (OR) for success: 7.07]. Euclidean distance (6.1 vs. 12 mm, P  < 0.0001) and lateral deviation (3.7 vs. 9.2 mm, P  < 0.0001) were significantly smaller using augmented reality. Augmented reality-guided puncture was significantly faster than with the conventional landmark approach (52.5 vs. 67.5 s, P  = 0.0015). CONCLUSION: Augmented reality guidance significantly improved the accuracy and success in an experimental phantom model of epidural puncture. With further technical development, augmented reality guidance might prove helpful in anatomically challenging neuraxial procedures.

Augmented reality-assisted craniofacial reconstruction in skull base lesions - an innovative technique for single-step resection and cranioplasty in neurosurgery.

Defects of the cranial vault often require cosmetic reconstruction with patient-specific implants, particularly in cases of craniofacial involvement. However, fabrication takes time and is expensive; therefore, efforts must be made to develop more rapidly available and more cost-effective alternatives. The current study investigated the feasibility of an augmented reality (AR)-assisted single-step procedure for repairing bony defects involving the facial skeleton and the skull base. In an experimental setting, nine neurosurgeons fabricated AR-assisted and conventionally shaped ("freehand") implants from polymethylmethacrylate (PMMA) on a skull model with a craniofacial bony defect. Deviations of the surface profile in comparison with the original model were quantified by means of volumetry, and the cosmetic results were evaluated using a multicomponent scoring system, each by two blinded neurosurgeons. Handling the AR equipment proved to be quite comfortable. The median volume deviating from the surface profile of the original model was low in the AR-assisted implants (6.40 cm3) and significantly reduced in comparison with the conventionally shaped implants (13.48 cm3). The cosmetic appearance of the AR-assisted implants was rated as very good (median 25.00 out of 30 points) and significantly improved in comparison with the conventionally shaped implants (median 14.75 out of 30 points). Our experiments showed outstanding results regarding the possibilities of AR-assisted procedures for single-step reconstruction of craniofacial defects. Although patient-specific implants still represent the gold standard in esthetic aspects, AR-assisted procedures hold high potential for an immediately and widely available, cost-effective alternative providing excellent cosmetic outcomes.

Stimulated Raman histology in the neurosurgical workflow of a major European neurosurgical center - part A.

Histopathological diagnosis is the current standard for the classification of brain and spine tumors. Raman spectroscopy has been reported to allow fast and easy intraoperative tissue analysis. Here, we report data on the intraoperative implementation of a stimulated Raman histology (SRH) as an innovative strategy offering intraoperative near real-time histopathological analysis. A total of 429 SRH images from 108 patients were generated and analyzed by using a Raman imaging system (Invenio Imaging Inc.). We aimed at establishing a dedicated workflow for SRH serving as an intraoperative diagnostic, research, and quality control tool in the neurosurgical operating room (OR). First experiences with this novel imaging modality were reported and analyzed suggesting process optimization regarding tissue collection, preparation, and imaging. The Raman imaging system was rapidly integrated into the surgical workflow of a large neurosurgical center. Within a few minutes of connecting the device, the first high-quality images could be acquired in a "plug-and-play" manner. We did not encounter relevant obstacles and the learning curve was steep. However, certain prerequisites regarding quality and acquisition of tissue samples, data processing and interpretation, and high throughput adaptions must be considered. Intraoperative SRH can easily be integrated into the workflow of neurosurgical tumor resection. Considering few process optimizations that can be implemented rapidly, high-quality images can be obtained near real time. Hence, we propose SRH as a complementary tool for the diagnosis of tumor entity, analysis of tumor infiltration zones, online quality and safety control and as a research tool in the neurosurgical OR.

Neuropathological interpretation of stimulated Raman histology images of brain and spine tumors: part B.

Intraoperative histopathological examinations are routinely performed to provide neurosurgeons with information about the entity of tumor tissue. Here, we quantified the neuropathological interpretability of stimulated Raman histology (SRH) acquired using a Raman laser imaging system in a routine clinical setting without any specialized training or prior experience. Stimulated Raman scattering microscopy was performed on 117 samples of pathological tissue from 73 cases of brain and spine tumor surgeries. A board-certified neuropathologist - novice in the interpretation of SRH - assessed image quality by scoring subjective tumor infiltration and stated a diagnosis based on the SRH images. The diagnostic accuracy was determined by comparison to frozen hematoxylin-eosin (H&E)-stained sections and the ground truth defined as the definitive neuropathological diagnosis. The overall SRH imaging quality was rated high with the detection of tumor cells classified as inconclusive in only 4.2% of all images. The accuracy of neuropathological diagnosis based on SRH images was 87.7% and was non-inferior to the current standard of fast frozen H&E-stained sections (87.3 vs. 88.9%, p = 0.783). We found a substantial diagnostic correlation between SRH-based neuropathological diagnosis and H&E-stained frozen sections (κ = 0.8). The interpretability of intraoperative SRH imaging was demonstrated to be equivalent to the current standard method of H&E-stained frozen sections. Further research using this label-free innovative alternative vs. conventional staining is required to determine to which extent SRH-based intraoperative decision-making can be streamlined in order to facilitate the advancement of surgical neurooncology.

Stereotactic cysto-ventricular catheters in craniopharyngiomas: an effective minimally invasive method to improve visual impairment and achieve long-term cyst volume reduction.

Craniopharyngiomas are typically located in the sellar region and frequently contain space-occupying cysts. They usually cause visual impairment and endocrine disorders. Due to the high potential morbidity associated with radical resection, several less invasive surgical approaches have been developed. This study investigated stereotactic-guided implantation of cysto-ventricular catheters (CVC) as a new method to reduce and control cystic components. Twelve patients with cystic craniopharyngiomas were treated with CVC in our hospital between 04/2013 and 05/2017. The clinical and radiological data were retrospectively analysed to evaluate safety aspects as well as ophthalmological and endocrine symptoms. The long-term development of tumour and cyst volumes was assessed by volumetry. The median age of our patients was 69.0 years and the median follow-up period was 41.0 months. Volumetric analyses demonstrated a mean reduction of cyst volume of 64.2% after CVC implantation. At last follow-up assessment, there was a mean reduction of cyst volume of 92.0% and total tumour volume of 85.8% after completion of radiotherapy. Visual acuity improved in 90% of affected patients, and visual field defects improved in 70% of affected patients. No patient showed ophthalmological deterioration after surgery, and endocrine disorders remained stable. Stereotactic implantation of CVC proved to be a safe minimally invasive method for the long-term reduction of cystic components with improved ophthalmological symptoms. The consequential decrease of total tumour volumes optimised conditions for adjuvant radiotherapy. Given the low surgical morbidity and the effective drainage of tumour cysts, this technique should be considered for the treatment of selected cystic craniopharyngiomas.

In vivo-assessment of the human temporal network: Evidence for asymmetrical effective connectivity.

The human temporal lobe is a multimodal association area which plays a key role in various aspects of cognition, particularly in memory formation and spatial navigation. Functional and anatomical connectivity of temporal structures is thus a subject of intense research, yet by far underexplored in humans due to ethical and technical limitations. We assessed intratemporal cortico-cortical interactions in the living human brain by means of single pulse electrical stimulation, an invasive method allowing mapping effective intracortical connectivity with a high spatiotemporal resolution. Eighteen subjects with normal anterior-mesial temporal MR imaging undergoing intracranial presurgical epilepsy diagnostics with multiple depth electrodes were included. The investigated structures were temporal pole, hippocampus, amygdala and parahippocampal gyrus. Intratemporal cortical connectivity was assessed as a function of amplitude of the early component of the cortico-cortical evoked potentials (CCEP). While the analysis revealed robust interconnectivity between all explored structures, a clear asymmetry in bidirectional connectivity was detected for the hippocampal network and for the connections between the temporal pole and parahippocampal gyrus. The amygdala showed bidirectional asymmetry only to the hippocampus. The provided evidence of asymmetrically weighed intratemporal effective connectivity in humans in vivo is important for understanding of functional interactions within the temporal lobe since asymmetries in the brain connectivity define hierarchies in information processing. The findings are in exact accord with the anatomical tracing studies in non-human primates and open a translational route for interventions employing modulation of temporal lobe function.

The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series.

INTRODUCTION: Deep brain stimulation alleviates tremor of various origins. The dentato-rubro-thalamic tract (DRT) has been suspected as a common tremor-reducing structure. Statistical evidence has not been obtained. We here report the results of an uncontrolled case series of patients with refractory tremor who underwent deep brain stimulation under tractographic assistance. METHODS: A total of 36 patients were enrolled (essential tremor (17), Parkinson's tremor (8), multiple sclerosis (7), dystonic head tremor (3), tardive dystonia (1)) and received 62 DBS electrodes (26 bilateral; 10 unilateral). Preoperatively, diffusion tensor magnetic resonance imaging sequences were acquired together with high-resolution anatomical T1W and T2W sequences. The DRT was individually tracked and used as a direct thalamic or subthalamic target. Intraoperative tremor reduction was graded on a 4-point scale (0 = no tremor reduction to 3 = full tremor control) and recorded together with the current amplitude, respectively. Stimulation point coordinates were recorded and compared to DRT. The relation of the current amplitude needed to reduce tremor was expressed as TiCR (tremor improvement per current ratio). RESULTS: Stimulation points of 241 were available for analysis. A total of 68 trajectories were tested (62 dB leads, 1.1 trajectories tested per implanted lead). Tremor improvement was significantly decreasing (p < 0.01) if the distance to both the border and the center of the DRT was increasing. On the initial trajectory, 56 leads (90.3%) were finally placed. Long-term outcomes were not part of this analysis. DISCUSSION: Tremor of various origins was acutely alleviated at different points along the DRT fiber tract (above and below the MCP plane) despite different tremor diseases. DRT is potentially a common tremor-reducing structure. Individual targeting helps to reduce brain penetrating tracts. TiCR characterizes stimulation efficacy and might help to identify an optimal stimulation point.

Postoperative neuroimaging analysis of DRT deep brain stimulation revision surgery for complicated essential tremor.

BACKGROUND: We report a patient who received conventional bilateral deep brain stimulation of the ventral intermediate nucleus of thalamus (Vim) for the treatment of medication refractory essential tremor (ET). After initial beneficial effects, therapeutic efficacy was lost due to a loss of control of his proximal trunkal and extremity tremor. The patient received successful diffusion tensor magnetic resonance imaging fiber tractographic (DTI FT)-assisted DBS revision surgery targeting the dentato-rubro-thalamic tract (DRT) in the subthalamic region (STR). OBJECTIVE: To report the concept of DTI FT-assisted DRT DBS revision surgery for ET and to show sophisticated postoperative neuroimaging analysis explaining improved symptom control. METHODS: Analysis was based on preoperative DTI sequences and postoperative helical computed tomography (hCT). Leads, stimulation fields, and fibers were reconstructed using commercial software systems (Elements, Brainlab AG, Feldkirchen, Germany; GUIDE XT, Boston Scientific Corp., Boston, MA, USA). RESULTS: The patient showed immediate and sustained tremor improvement after DTI FT-assisted revision surgery. Analysis of the two implantations (electrode positions in both instances) revealed a lateral and posterior shift in the pattern of modulation of the cortical fiber pathway projection after revision surgery as compared to initial implantation, explaining a more efficacious stimulation. CONCLUSIONS: Our work underpins a possible superiority of direct targeting approaches using advanced neuroimaging technologies to perform personalized DBS surgery. The evaluation of DBS electrode positions with the herein-described neuroimaging simulation technologies will likely improve targeting and revision strategies. Direct targeting with DTI FT-assisted approaches in a variety of indications is the focus of our ongoing research.

One-pass deep brain stimulation of dentato-rubro-thalamic tract and subthalamic nucleus for tremor-dominant or equivalent type Parkinson's disease.

BACKGROUND: Refractory tremor in tremor-dominant (TD) or equivalent-type (EQT) idiopathic Parkinson's syndrome (IPS) poses the challenge of choosing the best target region to for deep brain stimulation (DBS). While the subthalamic nucleus is typically chosen in younger patients as the target for dopamine-responsive motor symptoms, it is more complicated if tremor does not (fully) respond under trial conditions. In this report, we present the first results from simultaneous bilateral DBS of the DRT (dentato-rubro-thalamic tract) and the subthalamic nucleus (STN) in two elderly patients with EQT and TD IPS and dopamine-refractory tremor. METHODS: Two patients received bilateral octopolar DBS electrodes in the STN additionally traversing the DRT region. Achieved electrode positions were determined with helical CT, overlaid onto DTI tractography data, and compared with clinical data of stimulation response. RESULTS: Both patients showed immediate and sustained improvement of their tremor, bilaterally. CONCLUSIONS: The proposed approach appears to be safe and feasible and a combined stimulation of the two target regions was performed tailored to the patients' symptoms. Clinically, no neuropsychiatric effects were seen. Our pilot data suggest a viable therapeutic option to treat the subgroup of TD and EQT IPS and with tremor as the predominant symptom. A clinical study to further investigate this approach ( OPINION: www.clinicaltrials.gov ; NCT02288468) is the focus of our ongoing research.

Safety profile of subdural and depth electrode implantations in invasive EEG exploration of drug-resistant focal epilepsy.

PURPOSE: To analyze the safety profile of subdural and depth electrode implantation in a large monocentric cohort of patients of all ages undergoing intracranial EEG exploration because of drug resistant focal epilepsy diagnosed and implanted by a constant team of epileptologists and neurosurgeons. METHODS: We retrospectively analyzed data from 452 implantations in 420 patients undergoing invasive presurgical evaluation at the Freiburg Epilepsy Center from 1999 to 2019 (n = 160 subdural electrodes, n = 156 depth electrodes and n = 136 combination of both approaches). Complications were classified as hemorrhage with or without clinical manifestations, infection-associated and other complications. Furthermore, possible risk factors (age, duration of invasive monitoring, number of electrode contacts used) and changes in complication rates during the study period were analyzed. RESULTS: The most frequent complications in both implantation groups were hemorrhages. Subdural electrode explorations caused significantly more symptomatic hemorrhages and required more operative interventions (SDE 9.9%, DE 0.3%, p < 0.05). Hemorrhage risk was higher for grids with 64 contacts than for smaller grids (p < 0.05). The infection rate was very low (0,2%). A transient neurological deficit occurred in 8.8% of all implantations and persisted for at least 3 months in 1.3%. Transient, but not persistent neurological deficits were more common in patients with implanted subdural electrodes than in the depth electrode group. CONCLUSION: The use of subdural electrodes was associated with a higher risk of hemorrhage and transient neurological symptoms. However persistent deficits were rare with either approach, demonstrating that intracranial investigations using either subdural electrodes or depth electrodes carry acceptable risks in patients with drug-resistant focal epilepsy.

Accuracy of augmented reality-guided drainage versus stereotactic and conventional puncture in an intracerebral hemorrhage phantom model.

BACKGROUND: Minimally invasive intracranial drain placement is a common neurosurgical emergency procedure in patients with intracerebral hemorrhage (ICH). We aimed to retrospectively investigate the accuracy of conventional freehand (bedside) hemorrhage drain placement and to prospectively compare the accuracy of augmented/mixed reality-guided (AR) versus frame-based stereotaxy-guided (STX) and freehand drain placement in a phantom model. METHODS: A retrospective, single-center analysis evaluated the accuracy of drain placement in 73 consecutive ICH with a visual rating of postinterventional CT data. In a head phantom with a simulated deep ICH, five neurosurgeons performed four punctures for each technique: STX, AR, and the freehand technique. The Euclidean distance to the target point and the lateral deviation of the achieved trajectory from the planned trajectory at target point level were compared between the three methods. RESULTS: Analysis of the clinical cases revealed an optimal drainage position in only 46/73 (63%). Correction of the drain was necessary in 23/73 cases (32%). In the phantom study, accuracy of AR was significantly higher than the freehand method (P<0.001 for both Euclidean and lateral distances). The Euclidean distance using AR (median 3 mm) was close to that using STX (median 1.95 mm; P=0.023). CONCLUSIONS: We demonstrated that the accuracy of the freehand technique was low and that subsequent position correction was common. In a phantom model, AR drainage placement was significantly more precise than the freehand method. AR has great potential to increase precision of emergency intracranial punctures in a bedside setting.

Application of Augmented Reality in Percutaneous Procedures-Rhizotomy of the Gasserian Ganglion.

BACKGROUND: Percutaneous rhizotomy of the Gasserian ganglion for trigeminal neuralgia is an effective therapeutic procedure. Yet, landmark-guided cannulation of the foramen ovale is manually challenging and difficult to learn. OBJECTIVE: To overcome these limitations, we assessed the feasibility and accuracy of an augmented reality (AR)-guided puncture of the foramen ovale. METHODS: A head phantom with soft tissue structures of the facial area was built. A three-dimensional (3D)-dataset of the phantom was generated using a stereotactic planning workstation. An optimal trajectory to the foramen ovale was created and then transferred to an AR headset. A total of 2 neurosurgeons and 2 neuroradiologists independently performed 8 AR-guided and 8 landmark-guided cannulations of the foramen ovale, respectively. For each AR-guided cannulation, the hologram was manually aligned with the phantom. Accuracy of the cannulation was evaluated using the Euclidean distance to the target point as well as the lateral deviation of the achieved trajectory from the planned trajectory at target point level. RESULTS: With the help of AR guidance, a successful cannulation of the foramen ovale was achieved in 90.6% compared to the purely landmark-based method with 18.8%. Euclidean distance and lateral deviation were significantly lower with AR guidance than landmark guidance (P < .01). CONCLUSION: AR greatly improved accuracy of simulated percutaneous rhizotomy of the Gasserian ganglion.

A subgaleal electrode array for neurostimulation allows the recording of relevant information in closed loop applications.

BACKGROUND: Neurostimulation is an emerging treatment option for patients resistant to pharmacotherapy and ineligible for neurosurgical intervention. Compared to intracranial stimulation placement of electrodes in the subgaleal space offers a minimally invasive option for long-term seizure monitoring for responsive systems. NEW METHOD: It was investigated, whether electrode contacts of a device being developed as a stimulation system placed in the subgaleal space are suited for recording of EEG activity for seizure detection. EEG was recorded intraoperatively in four participants participating in a clinical trial during the insertion of the device. Quantitative parameters like electrode impedance, signal amplitude ranges and amplitude spectra were determined. Epileptiform patterns in the recordings were compared to patterns occurring in scalp EEG prior to device implantation. RESULTS: Electrode impedances, amplitude ranges for artefact free intervals and intervals containing artefacts were determined. Spectral analysis showed typical properties of EEG recordings with high amplitude content at low frequencies and a peak in the alpha band. No major noise except at power line frequency disturbed the recordings. In two patients, typical epileptiform patterns could be identified having similar characteristics as their respective scalp EEG recordings prior to device implantation. COMPARISON WITH EXISTING METHODS: New and less invasive electrode system compared to existing solutions for responsive neurostimulation. CONCLUSIONS: The subgaleal electrode system allows for high quality EEG recordings even in an hostile unfavorable environment like an operation theatre. For the design of a signal acquisition unit of a responsive system using subgaleal electrodes, specifications could be obtained.

Bilateral Globus Pallidus Internus Deep Brain Stimulation in a Case of Progressive Dystonia in Mohr-Tranebjaerg Syndrome with Bilateral Cochlear Implants.

INTRODUCTION: A 28-year-old man presented with a history of sensorineural deafness since early childhood treated with bilateral cochlear implants (CIs). He showed signs of debilitating dystonia that had been present since puberty. Dystonic symptoms, especially a protrusion of the tongue and bilateral hand tremor, had not responded to botulinum toxin therapy. We diagnosed Mohr-Tranebjaerg syndrome (MTS). METHODS AND MATERIAL: Deep brain stimulation (DBS) of the bilateral globus pallidus internus was performed predominantly with stereotaxic computed tomography angiography guidance under general anesthesia. Electrophysiology was used to identify the target regions and to guide DBS electrode placement. RESULTS: In the immediate postoperative course and stimulation, the patient showed marked improvement of facial, extremity, and cervical dystonia. More than 2 years after implantation, his dystonic symptoms had dramatically improved by 82%. DISCUSSION: MTS is a rare genetic disorder leading to sensorineural deafness, dystonia, and other symptoms. The use of DBS for the dystonia in MTS was previously described but not in the presence of bilateral CIs. CONCLUSION: DBS in MTS may be a viable option to treat debilitating dystonic symptoms. We describe successful DBS surgery, despite the presence of bilateral CIs, and stimulation therapy over 2 years.

One Pass Thalamic and Subthalamic Stimulation for Patients with Tremor-Dominant Idiopathic Parkinson Syndrome (OPINION): Protocol for a Randomized, Active-Controlled, Double-Blinded Pilot Trial.

BACKGROUND: Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. OBJECTIVE: This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. METHODS: This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson's Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson's disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. RESULTS: At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. CONCLUSIONS: The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the "quality of life" outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients' quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).

The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions.

Introduction: Despite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB) and the connectivity of the ventral tegmental area (VTA). A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB) - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.). This work aims at a normative description of the human MFB (and more detailed the slMFB) anatomy with respect to distant prefrontal connections and microstructural features. Methods and material: Healthy subjects (n = 55; mean age ±â€¯SD, 40 ±â€¯10 years; 32 females) underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments) of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB. Results: The MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right) and 98% (left) of the total relative fiber counts of the slMFB. Discussion: The anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and cortical prefrontal regions - but not to emotion-related regions on the medial cortical surface - realized via the superolateral branch of the MFB. Local tractography approaches appear to be inferior in showing these far-reaching projections. Since these local approaches are typically used for surgical targeting of DBS procedures, the here established detailed map might - as a normative template - guide future efforts to target deep brain stimulation of the slMFB in depression and other disorders related to dysfunction of reward and reward-associated learning.