Publications by authors named "Tobias Piroth"

21 Publications

  • Page 1 of 1

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Sci Rep 2021 Jan 22;11(1):2138. Epub 2021 Jan 22.

Department of Neurology, Medical Center, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.
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http://dx.doi.org/10.1038/s41598-021-81535-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822958PMC
January 2021

Navigated Deep Brain Stimulation Surgery: Evaluating the Combined Use of a Frame-Based Stereotactic System and a Navigation System.

Stereotact Funct Neurosurg 2021 19;99(1):48-54. Epub 2020 Oct 19.

Department of Stereotactic and Functional Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany,

Deep brain stimulation (DBS) is a complex surgical procedure that requires detailed anatomical knowledge. In many fields of neurosurgery navigation systems are used to display anatomical structures during an operation to aid performing these surgeries. In frame-based DBS, the advantage of visualization has not yet been evaluated during the procedure itself. In this study, we added live visualization to a frame-based DBS system, using a standard navigation system and investigated its accuracy and potential use in DBS surgery. As a first step, a phantom study was conducted to investigate the accuracy of the navigation system in conjunction with a frame-based approach. As a second step, 5 DBS surgeries were performed with this combined approach. Afterwards, 3 neurosurgeons and 2 neurologists with different levels of experience evaluated the potential use of the system with a questionnaire. Moreover, the additional personnel, costs and required set up time were noted and compared to 5 consecutive standard procedures. In the phantom study, the navigation system showed an inaccuracy of 2.1 mm (mean SD 0.69 mm). In the questionnaire, a mean of 9.4/10 points was awarded for the use of the combined approach as a teaching tool, a mean of 8.4/10 for its advantage in creating a 3-dimensional (3-D) map and a mean of 8/10 points for facilitating group discussions. Especially neurosurgeons and neurologists in training found it useful to better interpret clinical results and side effects (mean 9/10 points) and neurosurgeons appreciated its use to better interpret microelectrode recordings (mean 9/10 points). A mean of 6/10 points was awarded when asked if the benefits were worth the additional efforts. Initially 2 persons, then one additional person was required to set up the system with no relevant added time or costs. Using a navigation system for live visualization during frame-based DBS surgery can improve the understanding of the complex 3-D anatomy and many aspects of the procedure itself. For now, we would regard it as an excellent teaching tool rather than a necessity to perform DBS surgeries.
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http://dx.doi.org/10.1159/000510528DOI Listing
October 2020

Identifying controllable cortical neural markers with machine learning for adaptive deep brain stimulation in Parkinson's disease.

Neuroimage Clin 2020 12;28:102376. Epub 2020 Aug 12.

Brain State Decoding Lab (BrainLinks-BrainTools) and Autonomous Intelligent Systems, Dept. of Computer Science at the University of Freiburg, Germany; Artificial Cognitive Systems Lab, Artificial Intelligence Dept., Donders Institute for Brain, Cognition and Behaviour, Faculty of Social Sciences, Radboud University, Nijmegen, The Netherlands. Electronic address:

The identification of oscillatory neural markers of Parkinson's disease (PD) can contribute not only to the understanding of functional mechanisms of the disorder, but may also serve in adaptive deep brain stimulation (DBS) systems. These systems seek online adaptation of stimulation parameters in closed-loop as a function of neural markers, aiming at improving treatment's efficacy and reducing side effects. Typically, the identification of PD neural markers is based on group-level studies. Due to the heterogeneity of symptoms across patients, however, such group-level neural markers, like the beta band power of the subthalamic nucleus, are not present in every patient or not informative about every patient's motor state. Instead, individual neural markers may be preferable for providing a personalized solution for the adaptation of stimulation parameters. Fortunately, data-driven bottom-up approaches based on machine learning may be utilized. These approaches have been developed and applied successfully in the field of brain-computer interfaces with the goal of providing individuals with means of communication and control. In our contribution, we present results obtained with a novel supervised data-driven identification of neural markers of hand motor performance based on a supervised machine learning model. Data of 16 experimental sessions obtained from seven PD patients undergoing DBS therapy show that the supervised patient-specific neural markers provide improved decoding accuracy of hand motor performance, compared to group-level neural markers reported in the literature. We observed that the individual markers are sensitive to DBS therapy and thus, may represent controllable variables in an adaptive DBS system.
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http://dx.doi.org/10.1016/j.nicl.2020.102376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479445PMC
August 2020

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

Acta Neurochir (Wien) 2020 05 29;162(5):1053-1066. Epub 2020 Jan 29.

Department of Stereotactic and Functional Neurosurgery, Freiburg University Medical Center, Freiburg (i.Br.), Germany.

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.
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http://dx.doi.org/10.1007/s00701-020-04248-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156360PMC
May 2020

An Easy-to-Use and Fast Assessment of Patient-Specific DBS-Induced Changes in Hand Motor Control in Parkinson's Disease.

IEEE Trans Neural Syst Rehabil Eng 2019 10 16;27(10):2155-2163. Epub 2019 Sep 16.

For Parkinson's disease (PD), efficient and fast monitoring of fine motor function is fundamental for capturing transient phenomena induced by deep brain stimulation (DBS), thus, enabling a fast and accurate tuning of stimulation parameters. Tuning of DBS parameters is important for obtaining a patient-specific optimal clinical effect and to regularly compensate for disease progress. We propose a fine motor function assessment framework for capturing transient DBS-induced changes. The main goals are to obtain a fast, repeatable, objective, robust, and DBS-sensitive motor-score, in addition to a high-dimensional characterization of motor components by means of an interpretable data-driven model. To achieve this, we combine a hand motor-task, termed the copy-draw test, with a linear model for analyzing features extracted from the proposed task. The approach was tested with four patients totaling eight sessions analyzed. Our approach delivers a motor-score that is sensitive to DBS-induced changes in motor function. It can be applied repeatedly within seconds. The interpretability of the underlying machine learning model provides a direct overview of the feature relevance. This analysis allows to detect and characterize single movement components that are sensitive to DBS. The proposed assessment framework is an useful tool to push forward the data-driven identification of PD-relevant neural markers. Consequent to this end, the source code of the paradigm is made publicly available.
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http://dx.doi.org/10.1109/TNSRE.2019.2941453DOI Listing
October 2019

Automatic Segmentation of the Subthalamic Nucleus: A Viable Option to Support Planning and Visualization of Patient-Specific Targeting in Deep Brain Stimulation.

Oper Neurosurg (Hagerstown) 2019 11;17(5):497-502

Department of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany.

Background: Automatic segmentation is gaining relevancy in image-based targeting of neural structures.

Objective: To evaluate its feasibility, we retrospectively analyzed the concordance of magnetic resonance imaging (MRI)-based automatic segmentation of the subthalamic nucleus (STN) and intraoperative microelectrode recordings (MERs).

Methods: Electrodes (n = 60) for deep brain stimulation were implanted in the STN of patients (n = 30; median age 57 yr) with Parkinson disease (n = 29) or rapid-onset dystonia parkinsonism (n = 1). Elements (Brainlab, Munich, Germany) were used to segment the STN, using 2 volumetric T1 (±contrast) and volumetric T2 images as input. The stereotactic computed tomography was coregistered with the imaging, and the original stereotactic coordinates were imported. MERs (0.5-1 mm steps) along the anterior, central, and lateral trajectories were used to determine differences between the image-segmented STN boundary and MER-based STN entry and exit.

Results: Of 175 trajectories, 105 penetrated or touched (≤0.7 mm) the STN. The overall median deviation between the segmented STN boundary and electrophysiological recordings was 1.1 mm for MER-based STN entry and 2.0 mm for STN exit. Regarding the entry point of the STN, there was no statistically significant difference between MRI-based automatic segmentation and the electrophysiological trajectories analyzed with intraoperative MER. The exit point was significantly different between both methods in the central and lateral trajectories.

Conclusion: MRI-based automatic segmentation of the STN is a viable, patient-specific targeting approach that can be used alongside traditional targeting methods in deep brain stimulation to support preoperative planning and visualization of target structures and aid postoperative optimization of programming.
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http://dx.doi.org/10.1093/ons/opz015DOI Listing
November 2019

Atypical Presentation of Rapid-onset Dystonia-parkinsonism (DYT12) Unresponsive to Deep Brain Stimulation of the Subthalamic Nucleus.

Mov Disord Clin Pract 2018 Jul-Aug;5(4):427-429. Epub 2018 Apr 1.

Department of Neurology and Neuroscience, Medical Center - University of Freiburg, Medical Faculty University of Freiburg, Breisacher Straße 64 D-79106, Freiburg Germany.

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http://dx.doi.org/10.1002/mdc3.12605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336285PMC
April 2018

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

J Neurol Surg A Cent Eur Neurosurg 2019 Jan 5;80(1):44-48. Epub 2018 Oct 5.

Department of Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Freiburg, Germany.

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.
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http://dx.doi.org/10.1055/s-0038-1669472DOI Listing
January 2019

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.

JMIR Res Protoc 2018 Jan 30;7(1):e36. Epub 2018 Jan 30.

Department of Stereotactic and Functional Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.

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).
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http://dx.doi.org/10.2196/resprot.8341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811645PMC
January 2018

Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult.

Front Neurol 2017 4;8:108. Epub 2017 Apr 4.

Department of Neurology, University Hospital Freiburg, Freiburg im Breisgau, Germany.

Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.
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http://dx.doi.org/10.3389/fneur.2017.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378773PMC
April 2017

Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): Study Protocol of a Randomized Controlled Feasibility Trial.

JMIR Res Protoc 2016 Dec 22;5(4):e244. Epub 2016 Dec 22.

Department of Stereotactic and Functional Neurosurgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim-DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used.

Objective: This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient.

Methods: The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg.

Results: Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment.

Conclusions: The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery.

Clinicaltrial: ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS).
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http://dx.doi.org/10.2196/resprot.6885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216255PMC
December 2016

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

Acta Neurochir (Wien) 2016 Apr 15;158(4):773-781. Epub 2016 Feb 15.

Department of Stereotactic and Functional Neurosurgery, Freiburg University Medical Center, Freiburg, Germany.

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.
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http://dx.doi.org/10.1007/s00701-016-2725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791468PMC
April 2016

Organization of the human fetal subpallium.

Front Neuroanat 2013 16;7:54. Epub 2014 Jan 16.

Department of Neurology, University Freiburg - Medical Center Freiburg, Germany.

The subpallium comprises large parts of the basal ganglia including striatum and globus pallidus. Genes and factors involved in the development of the subpallium have been extensively studied in most vertebrates, including amphibians, birds, and rodents. However, our knowledge on patterning of the human subpallium remains insufficient. Using double fluorescent immunohistochemistry, we investigated the protein distribution of transcription factors involved in patterning of the subventricular zone (SVZ) in the human forebrain at late embryonic development. Furthermore, we compared the development of cortical and striatal precursors between human fetal brain and E14 and E16 fetal rat brains. Our results reveal that DLX2 marks SVZ precursors in the entire subpallium. Individual subpallial subdomains can be identified based on co-expression of DLX2 with either PAX6 or NKX2-1. SVZ precursors in the dorsal LGE and preopto-hypothalamic boundary are characterized by DLX2/PAX6 co-expression, while precursors in the MGE and preoptic region co-express DLX2/NKX2-1. SVZ precursors in the ventral LGE are DLX2(+)/PAX6(-)/NKX2-1(-). In terms of staging comparisons, the development of the corpus striatum in the human fetal brain during late embryonic stages corresponds well with the development of the striatum observed in E14 fetal rat brains. Our study demonstrates that the pattern underlying the development of the subpallium is highly conserved between rodents and humans and suggests a similar function for these factors in human brain development. Moreover, our data directly influence the application of ganglionic eminence derived human tissue for cell therapeutic approaches in neurodegenerative disorders such as Huntington's disease.
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http://dx.doi.org/10.3389/fnana.2013.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893616PMC
January 2014

Hypokinesia upon Pallidal Deep Brain Stimulation of Dystonia: Support of a GABAergic Mechanism.

Front Neurol 2013 Dec 5;4:198. Epub 2013 Dec 5.

Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg , Freiburg , Germany.

In the past, many studies have documented the beneficial effects of deep brain stimulation (DBS) in the globus pallidus internus for treatment of primary segmental or generalized dystonia. Recently however, several reports focused on DBS-induced hypokinesia or freezing of gait (FOG) as a side effect in these patients. Here we report on two patients suffering from FOG after successful treatment of their dystonic movement disorder with pallidal high frequency stimulation (HFS). Several attempts to reduce the FOG resulted in worsening of the control of dystonia. In one patient levodopa treatment was initialized which was somewhat successful to relieve FOG. We discuss the possible mechanisms of hypokinetic side effects of pallidal DBS which can be explained by the hypothesis of selective GABA release as the mode of action of HFS. Pallidal HFS is also effective in treating idiopathic Parkinson's disease as a hypokinetic disorder which at first sight seems to be a paradox. In our view, however, the GABAergic hypothesis can explain this and other clinical observations.
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http://dx.doi.org/10.3389/fneur.2013.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851850PMC
December 2013

Donor age dependent graft development and recovery in a rat model of Huntington's disease: histological and behavioral analysis.

Behav Brain Res 2013 Nov 3;256:56-63. Epub 2013 Aug 3.

Lab of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg - Medical Centre, Freiburg, Germany.

Neural cell replacement therapy using fetal striatal cells has provided evidence of disease modification in clinical trials in Huntington's disease (HD) patients, although the results have been inconsistent. One of the contributing factors to the variable outcome could be the different capacity of transplanted cells derived from the primordial striatum to proliferate and maturate into striatal projection neurons. Based on the rodent lesion model of HD, the current study investigated how intrastriatal-striatal grafts from variable aged donors develop in vivo and how they influence functional recovery. Young adult female Sprague-Dawley rats were lesioned unilaterally in the dorso-striatum with quinolinic acid (0.12 M) and transplanted 14 days later with single cell suspension grafts equivalent of one whole ganglionic eminence (WGE) from donors of embryonic developmental age E13, E14, or E15; animals with or without striatal lesion served as controls. All animals were tested on the Cylinder and the Corridor tests, as well as on apomorphine-induced rotation at baseline, post-lesion/pre-grafting, and at 6 and 10 weeks post-grafting. A week prior to perfusion, a sub-group in each grafted group received fluorogold injections into the ipsilateral globus pallidus to study graft efferent projections. In summary, the data demonstrates that the age of the embryonic donor tissue has an impact on both the graft mediated functional recovery, and on the in vivo cellular composition of the striatal transplant. E13 tissue grafts gave the best overall outcome indicating that WGE from different donor ages have different potential to promote functional recovery. Understanding the stages and process in rodent striatal development could improve tissue selection in clinical trials of cell therapy in HD.
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http://dx.doi.org/10.1016/j.bbr.2013.07.053DOI Listing
November 2013

Transplantation of human fetal tissue for neurodegenerative diseases: validation of a new protocol for microbiological analysis and bacterial decontamination.

Cell Transplant 2014 29;23(8):995-1007. Epub 2013 Apr 29.

Department of Neurology, University Freiburg - Medical Center, Freiburg im Breisgau, Germany.

Restorative cell therapy concepts in neurodegenerative diseases are aimed at replacing lost neurons. Despite advances in research on pluripotent stem cells, fetal tissue from routine elective abortions is still regarded as the only safe cell source. Progenitor cells isolated from distinct first-trimester fetal CNS regions have already been used in clinical trials and will be used again in a new multicenter trial funded by the European Union (TRANSEURO). Bacterial contamination of human fetal tissue poses a potential risk of causing infections in the brain of the recipient. Thus, effective methods of microbial decontamination and validation of these methods are required prior to approval of a neurorestorative cell therapy trial. We have developed a protocol consisting of subsequent washing steps at different stages of tissue processing. Efficacy of microbial decontamination was assessed on rat embryonic tissue incubated with high concentrations of defined microbe solutions including representative bacterial and fungal species. Experimental microbial contamination was reduced by several log ranks. Subsequently, we have analyzed the spectrum of microbial contamination and the effect of subsequent washing steps on aborted human fetal tissue; 47.7% of the samples taken during human fetal tissue processing were positive for a microbial contamination, but after washing, no sample exhibited bacterial growth. Our data suggest that human fetal tissue for neural repair can carry microbes of various species, highlighting the need for decontamination procedures. The decontamination protocol described in this report has been shown to be effective as no microbes could be detected at the end of the procedure.
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http://dx.doi.org/10.3727/096368913X666449DOI Listing
May 2015

Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens.

Neurobiol Dis 2013 Jan 24;49:118-27. Epub 2012 Aug 24.

Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden. Electronic address:

Human fetal midbrain tissue grafting has provided proof-of-concept for dopamine cell replacement therapy (CRT) in Parkinson's disease (PD). However, limited tissue availability has hindered the development and widespread use of this experimental therapy. Here we present a method for generating large numbers of midbrain dopaminergic (DA) neurons based on expanding and differentiating neural stem/progenitor cells present in the human ventral midbrain (hVM) tissue. Our results show that hVM neurospheres (hVMN) with low cell numbers, unlike their rodent counterparts, expand the total number of cells 3-fold, whilst retaining their capacity to differentiate into midbrain DA neurons. Moreover, Wnt5a promoted DA differentiation of expanded cells resulting in improved morphological maturation, midbrain DA marker expression, DA release and electrophysiological properties. This method results in cell preparations that, after expansion and differentiation, can contain 6-fold more midbrain DA neurons than the starting VM preparation. Thus, our results provide evidence that by improving expansion and differentiation of progenitors present in the hVM it is possible to greatly enrich cell preparations for DA neurons. This method could substantially reduce the amount of human fetal midbrain tissue necessary for CRT in patients with PD, which could have major implications for the widespread adoption of this approach.
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http://dx.doi.org/10.1016/j.nbd.2012.08.006DOI Listing
January 2013

Restoration of the striatal circuitry: from developmental aspects toward clinical applications.

Front Cell Neurosci 2012 19;6:16. Epub 2012 Apr 19.

Division of Stereotactic Neurosurgery, Department of General Neurosurgery, University Freiburg - Medical Center Freiburg im Breisgau, Germany.

In the basal ganglia circuitry, the striatum is a highly complex structure coordinating motor and cognitive functions and it is severely affected in Huntington's disease (HD) patients. Transplantation of fetal ganglionic eminence (GE) derived precursor cells aims to restore neural circuitry in the degenerated striatum of HD patients. Pre-clinical transplantation in genetic and lesion HD animal models has increased our knowledge of graft vs. host interactions, and clinical studies have been shown to successfully reduce motor and cognitive effects caused by the disease. Investigating the molecular mechanisms of striatal neurogenesis is a key research target, since novel strategies aim on generating striatal neurons by differentiating embryonic stem cells or by reprogramming somatic cells as alternative cell source for neural transplantation.
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http://dx.doi.org/10.3389/fncel.2012.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329876PMC
October 2012

Neurorehabilitation with neural transplantation.

Neurorehabil Neural Repair 2010 Oct 20;24(8):692-701. Epub 2010 Jul 20.

University Hospital Freiburg, Freiburg, Germany.

Cell replacement therapy has been tested clinically in Parkinson's disease (PD) and Huntington's disease (HD), epilepsy, spinal cord injury, and stroke. The clinical outcomes have been variable, perhaps partly because of the differing levels of preclinical, basic experimental evidence that was available prior to the trials. The most promising results have been seen in PD trials, with encouraging ones in HD. A common feature of most trials is that they have concentrated on the biological and technical aspects of transplantation without presupposing that the outcomes might be influenced by events after the surgery. The growing evidence of plasticity demonstrated by the brain and grafts in response to environmental and training stimuli such as rehabilitation interventions has been mostly neglected throughout the clinical application of cell therapy. This review suggests that a different approach may be required to maximize recovery: postoperative experiences, including rehabilitation with explicit behavioral retraining, could have marked direct as well as positive secondary effects on the integration and function of grafted cells in the host neural system. The knowledge gained about brain plasticity following brain damage needs to be linked with what we know about promoting intrinsic recovery processes and how this can boost neurobiological and surgical strategies for repair at the clinical level. With proof of principle now established, a rich area for innovative research with profound therapeutic application is open for investigation.
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http://dx.doi.org/10.1177/1545968310363586DOI Listing
October 2010

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors.

BMC Cancer 2010 Feb 2;10:30. Epub 2010 Feb 2.

Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Str, 64, 79106 Freiburg im Breisgau, Germany.

Background: The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.

Methods: We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model.

Results: The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off).

Conclusion: In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.
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http://dx.doi.org/10.1186/1471-2407-10-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837009PMC
February 2010