Publications by authors named "Georgios Naros"

40 Publications

Time-Frequency Representation of Motor Evoked Potentials in Brain Tumor Patients.

Front Neurol 2020 5;11:633224. Epub 2021 Feb 5.

Neurosurgical Clinic, Department of Neurosurgery and Neurotechnology, Eberhard Karls University of Tuebingen, Tuebingen, Germany.

The integrity of the motor system can be examined by applying navigated transcranial magnetic stimulation (nTMS) to the cortex. The corresponding motor-evoked potentials (MEPs) in the target muscles are mirroring the status of the human motor system, far beyond corticospinal integrity. Commonly used time domain features of MEPs (e.g., peak-to-peak amplitudes and onset latencies) exert a high inter-subject and intra-subject variability. Frequency domain analysis might help to resolve or quantify disease-related MEP changes, e.g., in brain tumor patients. The aim of the present study was to describe the time-frequency representation of MEPs in brain tumor patients, its relation to clinical and imaging findings, and the differences to healthy subject. This prospective study compared 12 healthy subjects with 12 consecutive brain tumor patients (with and without a paresis) applying nTMS mapping. Resulting MEPs were evaluated in the time series domain (i.e., amplitudes and latencies). After transformation into the frequency domain using a Morlet wavelet approach, event-related spectral perturbation (ERSP), and inter-trial coherence (ITC) were calculated and compared to diffusion tensor imaging (DTI) results. There were no significant differences in the time series characteristics between groups. MEPs were projecting to a frequency band between 30 and 300 Hz with a local maximum around 100 Hz for both healthy subjects and patients. However, there was ERSP reduction for higher frequencies (>100 Hz) in patients in contrast to healthy subjects. This deceleration was mirrored in an increase of the inter-peak MEP latencies. Patients with a paresis showed an additional disturbance in ITC in these frequencies. There was no correlation between the CST integrity (as measured by DTI) and the MEP parameters. Time-frequency analysis may provide additional information above and beyond classical MEP time domain features and the status of the corticospinal system in brain tumor patients. This first evaluation indicates that brain tumors might affect cortical physiology and the responsiveness of the cortex to TMS resulting in a temporal dispersion of the corticospinal transmission.
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http://dx.doi.org/10.3389/fneur.2020.633224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894199PMC
February 2021

Holmes tremor: a delayed complication after resection of brainstem cavernomas.

J Neurosurg 2020 Dec 11:1-11. Epub 2020 Dec 11.

1Neurosurgery, Great Metropolitan Hospital Niguarda, Milan.

Objective: In this paper, the authors aimed to illustrate how Holmes tremor (HT) can occur as a delayed complication after brainstem cavernoma resection despite strict adherence to the safe entry zones (SEZs).

Methods: After operating on 2 patients with brainstem cavernoma at the Great Metropolitan Hospital Niguarda in Milan and noticing a similar pathological pattern postoperatively, the authors asked 10 different neurosurgery centers around the world to identify similar cases, and a total of 20 were gathered from among 1274 cases of brainstem cavernomas. They evaluated the tremor, cavernoma location, surgical approach, and SEZ for every case. For the 2 cases at their center, they also performed electromyographic and accelerometric recordings of the tremor and evaluated the post-operative tractographic representation of the neuronal pathways involved in the tremorigenesis. After gathering data on all 1274 brainstem cavernomas, they performed a statistical analysis to determine if the location of the cavernoma is a potential predicting factor for the onset of HT.

Results: From the analysis of all 20 cases with HT, it emerged that this highly debilitating tremor can occur as a delayed complication in patients whose postoperative clinical course has been excellent and in whom surgical access has strictly adhered to the SEZs. Three of the patients were subsequently effectively treated with deep brain stimulation (DBS), which resulted in complete or almost complete tremor regression. From the statistical analysis of all 1274 brainstem cavernomas, it was determined that a cavernoma location in the midbrain was significantly associated with the onset of HT (p < 0.0005).

Conclusions: Despite strict adherence to SEZs, the use of intraoperative neurophysiological monitoring, and the immediate success of a resective surgery, HT, a severe neurological disorder, can occur as a delayed complication after resection of brainstem cavernomas. A cavernoma location in the midbrain is a significant predictive factor for the onset of HT. Further anatomical and neurophysiological studies will be necessary to find clues to prevent this complication.
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http://dx.doi.org/10.3171/2020.7.JNS201352DOI Listing
December 2020

Time Efficiency in Stereotactic Robot-Assisted Surgery: An Appraisal of the Surgical Procedure and Surgeon's Learning Curve.

Stereotact Funct Neurosurg 2021 5;99(1):25-33. Epub 2020 Oct 5.

Department of Neurosurgery, Eberhardt Karls University of Tübingen, Tübingen, Germany,

Background: Frame-based stereotactic procedures are still the gold standard in neurosurgery. However, there is an increasing interest in robot-assisted technologies. Introducing these increasingly complex tools in the clinical setting raises the question about the time efficiency of the system and the essential learning curve of the surgeon.

Methods: This retrospective study enrolled a consecutive series of patients undergoing a robot-assisted procedure after first system installation at one institution. All procedures were performed by the same neurosurgeon to capture the learning curve. The objective read-out were the surgical procedure time (SPT), the skin-to-skin time, and the intraoperative registration time (IRT) after laser surface registration (LSR), bone fiducial registration (BFR), and skin fiducial registration (SFR), as well as the quality of the registration (as measured by the fiducial registration error [FRE]). The time measures were compared to those for a patient group undergoing classic frame-based stereotaxy.

Results: In the first 7 months, we performed 31 robot-assisted surgeries (26 biopsies, 3 stereotactic electroencephalography [SEEG] implantations, and 2 endoscopic procedures). The SPT was depending on the actual type of surgery (biopsies: 85.0 ± 36.1 min; SEEG: 154.9 ± 75.9 min; endoscopy: 105.5 ± 1.1 min; p = 0.036). For the robot-assisted biopsies, there was a significant reduction in SPT within the evaluation period, reaching the level of frame-based surgeries (58.1 ± 17.9 min; p < 0.001). The IRT was depending on the applied registration method (LSR: 16.7 ± 2.3 min; BFR: 3.5 ± 1.1 min; SFR: 3.5 ± 1.6 min; p < 0.001). In contrast to BFR and SFR, there was a significant reduction in LSR time during that period (p = 0.038). The FRE differed between the applied registration methods (LSR: 0.60 ± 0.17 mm; BFR: 0.42 ± 0.15 mm; SFR: 2.17 ± 0.78 mm; p < 0.001). There was a significant improvement in LSR quality during the evaluation period (p = 0.035).

Conclusion: Introducing stereotactic, robot-assisted surgery in an established clinical setting initially necessitates a prolonged intraoperative preparation time. However, there is a steep learning curve during the first cases, reaching the time level of classic frame-based stereotaxy. Thus, a stereotactic robot can be integrated into daily routine within a decent period of time, thereby expanding the neurosurgeons' armamentarium, especially for procedures with multiple trajectories.
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http://dx.doi.org/10.1159/000510107DOI Listing
October 2020

Occurrence and management of postoperative pneumocephalus using the semi-sitting position in vestibular schwannoma surgery.

Acta Neurochir (Wien) 2020 11 25;162(11):2629-2636. Epub 2020 Jul 25.

Department of Neurosurgery, Eberhardt Karls University, Hoppe-Seyler-Straße 3, 72076, Tuebingen, Germany.

Background: The semi-sitting position in neurosurgical procedures is still under debate due to possible complications such as venous air embolism (VAE) or postoperative pneumocephalus (PP). Studies reporting a high frequency of the latter raise the question about the clinical relevance (i.e., the incidence of tension pneumocephalus) and the efficacy of a treatment by an air replacement procedure.

Methods: This retrospective study enrolled 540 patients harboring vestibular schwannomas who underwent posterior fossa surgery in a supine (n = 111) or semi-sitting (n = 429) position. The extent of the PP was evaluated by voxel-based volumetry (VBV) and related to clinical predictive factors (i.e., age, gender, position, duration of surgery, and tumor size).

Results: PP with a mean volume of 32 ± 33 ml (range: 0-179.1 ml) was detected in 517/540 (96%) patients. The semi-sitting position was associated with a significantly higher PP volume than the supine position (40.3 ± 33.0 ml [0-179.1] and 0.8 ± 1.4 [0-10.2], p < 0.001). Tension pneumocephalus was observed in only 14/429 (3.3%) of the semi-sitting cases, while no tension pneumocephalus occurred in the supine position. Positive predictors for PP were higher age, male gender, and longer surgery duration, while large (T4) tumor size was established as a negative predictor. Air exchange via a twist-drill was only necessary in 14 cases with an intracranial air volume > 60 ml. Air replacement procedures did not add any complications or prolong the ICU stay.

Conclusion: Although pneumocephalus is frequently observed following posterior fossa surgery in semi-sitting position, relevant clinical symptoms (i.e., a tension pneumocephalus) occur in only very few cases. These cases are well-treated by an air evacuation procedure. This study indicates that the risk of postoperative pneumocephalus is not a contraindication for semi-sitting positioning.
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http://dx.doi.org/10.1007/s00701-020-04504-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550361PMC
November 2020

Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy.

Neuroimage 2020 09 20;218:116967. Epub 2020 May 20.

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, And Tübingen NeuroCampus, University of Tübingen, 72076, Tübingen, Germany. Electronic address:

Background: Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement.

Methods: We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 ​Hz, 90 ​μs, 3-5 ​V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones.

Results: ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders.

Conclusion: This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116967DOI Listing
September 2020

Online Mapping With the Deep Brain Stimulation Lead: A Novel Targeting Tool in Parkinson's Disease.

Mov Disord 2020 09 18;35(9):1574-1586. Epub 2020 May 18.

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, and Tübingen NeuroCampus, University of Tübingen, Tübingen, Germany.

Background: Beta-frequency oscillations (13-30 Hz) are a subthalamic hallmark in patients with Parkinson's disease, and there is increased interest in their utility as an intraoperative marker.

Objectives: The objectives of this study were to assess whether beta activity measured directly from macrocontacts of deep brain stimulation leads could be used (a) as an intraoperative electrophysiological approach for guiding lead placements and (b) for physiologically informed stimulation delivery.

Methods: Every millimeter along the surgical trajectory, local field-potential data were collected from each macrocontact, and power spectral densities were calculated and visualized (n = 39 patients). This was done for online intraoperative functional mapping and post hoc statistical analyses using 2 methods: generating distributions of spectral activity along surgical trajectories and direct delineation (presence versus lack) of beta peaks. In a subset of patients, this approach was corroborated by microelectrode recordings. Furthermore, the match rate between beta peaks at the final target position and the clinically determined best stimulation site were assessed.

Results: Subthalamic recording sites were delineated by both methods of reconstructing functional topographies of spectral activity along surgical trajectories at the group level (P < 0.0001). Beta peaks were detected when any portion of the 1.5 mm macrocontact was within the microelectrode-defined subthalamic border. The highest beta peak at the final implantation site corresponded to the site of active stimulation in 73.3% of hemispheres (P < 0.0001). In 93.3% of hemispheres, active stimulation corresponded to the first-highest or second-highest beta peak.

Conclusions: Online measures of beta activity with the deep brain stimulation macroelectrode can be used to inform surgical lead placement and contribute to optimization of stimulation programming procedures. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28093DOI Listing
September 2020

Detecting poststroke cortical motor maps with biphasic single- and monophasic paired-pulse TMS.

Brain Stimul 2020 Jul - Aug;13(4):1102-1104. Epub 2020 May 8.

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, And Tuebingen NeuroCampus, University of Tuebingen, Germany. Electronic address:

Background: Residual corticospinal connections are the precondition for poststroke motor recovery and necessary for targeted interventions. In severely affected patients, standard transcranial magnetic stimulation (TMS) may lead to false negative findings.

Objective: Detecting the cortical representation of paralyzed forearm muscles by applying different stimulation techniques and maps beyond the hotspot.

Methods: In seventeen chronic stroke patients with severe motor deficits, navigated biphasic single (SP) and monophasic paired-pulse (PP) TMS was applied at 100% stimulator output to an extended cortical area in the ipsilesional hemisphere, while recording surface EMG of the extensor carpi radialis muscle.

Results: In eleven patients, residual connectivity to the paralyzed forearm was detected with either mapping technique (five SP and PP, four PP only, two SP only). In five patients, connections originated from non-primary motor areas.

Conclusion: These results could be instrumental for identifying candidates and stimulation targets for novel neuromodulation interventions in the context of neurorehabilitation.
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http://dx.doi.org/10.1016/j.brs.2020.05.005DOI Listing
December 2020

Neurophysiology-Driven Parameter Selection in nTMS-Based DTI Tractography: A Multidimensional Mathematical Model.

Front Neurosci 2019 18;13:1373. Epub 2019 Dec 18.

Department of Neurosurgery, Eberhard Karls Universität Tübingen, Tübingen, Germany.

There is an increasing interest in preoperative diffusion tensor imaging-based fiber tracking (DTI-FT) to preserve function during surgeries in motor eloquent brain regions. However, DTI tractography is challenged by inherent presumptions during particular tracking steps [e.g., deterministic vs. probabilistic DTI, fractional anisotropy (FA) and fiber length (FL) thresholding] and the missing "ground truth" information. In the present study, we intended to establish an objective, neurophysiology-driven approach for parameter selection during DTI-FT of the corticospinal tract integrating both imaging and neurophysiological information. In ten patients with lesions in eloquent motor areas, preoperative navigated transcranial magnetic stimulation (nTMS) was performed, followed by individual deterministic DTI-FT from a grid of cortical seed points. We investigated over 300 combinations of FA and FL thresholds and applied subsequently a multidimensional mathematical modeling of this empirical data. Optimal DTI parameters were determined by the relationship between DTI-FT (i.e., number of fibers, NoF) and nTMS (i.e., amplitudes of motor-evoked potentials) results. Finally, neurophysiological DTI parameters and the resulting tractography were compared to the current standard approaches of deterministic DTI fiber tracking with a 75% and 50% FA and a FL threshold of 110 mm as well as with intraoperative direct cortical and subcortical stimulation. There was a good goodness-of-fit for the mathematical model ( = 0.68 ± 0 13; range: 0.59-0.97; = 8) except of two cases. Neurophysiology-driven parameter selection showed a high correlation between DTI-FT and nTMS results ( = 0.73 ± 0.16; range: 0.38-0.93). In comparison to the standard approach, the mathematically calculated thresholds resulted in a higher NoF in 75% of patients. In 50% of patients this approach helped to clarify the exact tract location or to detect additional functional tracts, which were not identified by the standard approach. This was confirmed by direct cortical or subcortical stimulation. The present study evaluates a novel user-independent method to extract objective DTI-FT parameters that were completely based on neurophysiological data. The findings suggest that this method may improve the specificity and sensitivity of DTI-FT and thereby overcome the disadvantages of current approaches.
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http://dx.doi.org/10.3389/fnins.2019.01373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930230PMC
December 2019

Brain State-dependent Gain Modulation of Corticospinal Output in the Active Motor System.

Cereb Cortex 2020 01;30(1):371-381

Division of Functional and Restorative Neurosurgery, and Tuebingen NeuroCampus, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.

The communication through coherence hypothesis suggests that only coherently oscillating neuronal groups can interact effectively and predicts an intrinsic response modulation along the oscillatory rhythm. For the motor cortex (MC) at rest, the oscillatory cycle has been shown to determine the brain's responsiveness to external stimuli. For the active MC, however, the demonstration of such a phase-specific modulation of corticospinal excitability (CSE) along the rhythm cycle is still missing. Motor evoked potentials in response to transcranial magnetic stimulation (TMS) over the MC were used to probe the effect of cortical oscillations on CSE during several motor conditions. A brain-machine interface (BMI) with a robotic hand orthosis allowed investigating effects of cortical activity on CSE without the confounding effects of voluntary muscle activation. Only this BMI approach (and not active or passive hand opening alone) revealed a frequency- and phase-specific cortical modulation of CSE by sensorimotor beta-band activity that peaked once per oscillatory cycle and was independent of muscle activity. The active MC follows an intrinsic response modulation in accordance with the communication through coherence hypothesis. Furthermore, the BMI approach may facilitate and strengthen effective corticospinal communication in a therapeutic context, for example, when voluntary hand opening is no longer possible after stroke.
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http://dx.doi.org/10.1093/cercor/bhz093DOI Listing
January 2020

Ki-67 labeling index and expression of p53 are non-predictive for invasiveness and tumor size in functional and nonfunctional pituitary adenomas.

Acta Neurochir (Wien) 2019 06 30;161(6):1149-1156. Epub 2019 Apr 30.

Department for Neurosurgery, University Hospital Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Background: It is still controversial whether an increased proliferation index is correlated with the tumor invasiveness of pituitary adenomas. A homogeneous large monocentric series of pituitary adenomas was retrospectively analyzed. The correlation between the proliferation indices (Ki-67 and p53 expression levels) and invasiveness and size of pituitary adenomas was investigated in primary operated and recurrent adenomas.

Method: Four hundred thirty-nine patients after resection of pituitary adenomas were retrospectively included (43 recurrent tumors, 196 null cell adenomas, 86 somatotroph adenomas, 55 corticotroph adenomas, 55 prolactinomas, 4 thyreotroph adenomas). The maximum tumor diameter and tumor invasiveness in Knosp grading were assessed and Ki-67 and p53 immunostaining was performed. The role of invasiveness was evaluated using a cumulative odds ordinal logistic regression. For calculating the effect of tumor size, a one-way analysis of variance (ANOVA) was conducted.

Results: Overall and in the subgroups, no significant correlation between proliferation indices and mean tumor diameter was found. No significant predictive expression value of Ki-67 and p53 on tumor invasiveness and in recurrent tumors could be demonstrated. There was a tendency that Ki-67 LI and p53 LI are higher in recurrent corticotroph adenomas and lactotroph adenomas but values did not reach the significant level.

Conclusion: Invasive character of pituitary adenomas is neither correlated with increased Ki-67 LI nor with increased p53 expression. Proliferation parameters are independent from adenoma size at initial presentation. The partly elevated expression of Ki-67 in recurrent tumors underlines the clinical importance of the marker.
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http://dx.doi.org/10.1007/s00701-019-03879-4DOI Listing
June 2019

Intraoperative localization of spatially and spectrally distinct resting-state networks in Parkinson's disease.

J Neurosurg 2019 Mar 1;132(4):1234-1242. Epub 2019 Mar 1.

1Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for symptomatic Parkinson's disease (PD); the clinical benefit may not only mirror modulation of local STN activity but also reflect consecutive network effects on cortical oscillatory activity. Moreover, STN-DBS selectively suppresses spatially and spectrally distinct patterns of synchronous oscillatory activity within cortical-subcortical loops. These STN-cortical circuits have been described in PD patients using magnetoencephalography after surgery. This network information, however, is currently not available during surgery to inform the implantation strategy.The authors recorded spontaneous brain activity in 3 awake patients with PD (mean age 67 ± 14 years; mean disease duration 13 ± 7 years) during implantation of DBS electrodes into the STN after overnight withdrawal of dopaminergic medication. Intraoperative propofol was discontinued at least 30 minutes prior to the electrophysiological recordings. The authors used a novel approach for performing simultaneous recordings of STN local field potentials (LFPs) and multichannel electroencephalography (EEG) at rest. Coherent oscillations between LFP and EEG sensors were computed, and subsequent dynamic imaging of coherent sources was performed.The authors identified coherent activity in the upper beta range (21-35 Hz) between the STN and the ipsilateral mesial (pre)motor area. Coherence in the theta range (4-6 Hz) was detected in the ipsilateral prefrontal area.These findings demonstrate the feasibility of detecting frequency-specific and spatially distinct synchronization between the STN and cortex during DBS surgery. Mapping the STN with this technique may disentangle different functional loops relevant for refined targeting during DBS implantation.
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http://dx.doi.org/10.3171/2018.11.JNS181684DOI Listing
March 2019

Extended enhancement of corticospinal connectivity with concurrent cortical and peripheral stimulation controlled by sensorimotor desynchronization.

Brain Stimul 2018 Nov - Dec;11(6):1331-1335. Epub 2018 Aug 22.

Division of Functional and Restorative Neurosurgery, Tuebingen NeuroCampus, Eberhard Karls University Tuebingen, Germany. Electronic address:

Background: Pairing cortical and peripheral input during motor imagery (MI)-related sensorimotor desynchronization (ERD) modulates corticospinal excitability at the cortical representation (hotspot) of the imagined movement.

Objective: To determine the effects of this associative stimulation protocol on the cortical motor map beyond the hotspot.

Methods: In healthy subjects, peripheral stimulation through passive hand opening by a robotic orthosis and single-pulse transcranial magnetic stimulation to the respective cortical motor representation were applied in a brain-machine interface environment. State-dependency was investigated by concurrent, delayed or non-specific stimulation with respect to ERD in the beta-band (16-22 Hz) during MI of finger extension.

Results: Concurrent stimulation led to increased excitability of an extended motor map. Delayed and non-specific stimulation led to heterogeneous changes, i.e., opposite patterns of increased excitability in either the center or the periphery of the motor map.

Conclusion: These results could be instrumental in closed-loop, state-dependent stimulation in the context of neurorehabilitation.
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http://dx.doi.org/10.1016/j.brs.2018.08.012DOI Listing
May 2019

Three-dimensional accuracy of mandibular reconstruction by patient-specific pre-bent reconstruction plates using an "in-house" 3D-printer.

J Craniomaxillofac Surg 2018 Sep 1;46(9):1645-1651. Epub 2018 Jun 1.

Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. Siegmar Reinert, M.D., D.M.D., Ph.D.), University Hospital Tuebingen, Osianderstrasse 2-8, 72076, Tuebingen, Germany.

Purpose: The purpose of this study was to compare the three-dimensional accuracy of mandibular reconstruction following mandible continuity resection in patients treated with patient-specific, pre-bent reconstruction plates, using an 'in-house' 3D printer, with that in patients treated with conventional, intraoperatively bent plates.

Patients And Methods: We retrospectively analyzed 42 alloplastic mandibular reconstructions following continuity resection. 21 patients received patient-specific, pre-bent reconstruction plates using an in-house 3D printer. The control group consisted of 21 patients provided with intraoperatively bent reconstruction plates. Distances between corresponding anatomical landmarks on the mandibular angle and condyle (A-A', BB', CC', BC'), as well as the intercondylar angle (ICA), were measured and compared on the pre- and postoperative CT scans.

Results: Multivariate analysis of variance (MANOVA) showed significant multivariate main effect of group (F = 5.58, p = 0.001; Wilks lambda 0.564; partial η = 0.436), indicating more accurate postoperative results for the pre-bent group. Post-hoc comparison revealed significantly larger postoperative deviation in the distances between the mandibular angle and the intercondylar angle (ICA) for the intraoperatively bent group in comparison with the pre-bent group. However, there was no significant effect on the distance between the condyles.

Conclusions: Mandibular reconstructions employing patient-specific, pre-bent reconstruction plates made using an in-house 3D printer show significantly better three-dimensional accuracy compared with intraoperatively bent plates. The described method prevents rotational error of the mandibular angle and improves restoration of the physiological intercondylar angle in mandible reconstruction after continuity resection.
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http://dx.doi.org/10.1016/j.jcms.2018.05.047DOI Listing
September 2018

Postoperative Tinnitus After Vestibular Schwannoma Surgery Depends on Preoperative Tinnitus and Both Pre- and Postoperative Hearing Function.

Front Neurol 2018 12;9:136. Epub 2018 Mar 12.

Department of Neurosurgery, Eberhardt Karls University, Tuebingen, Germany.

Objective: Tinnitus is one of the most common symptoms before and/or after the surgical removal of a vestibular schwannoma (VS) affecting almost half of the patients. Although there is increasing evidence for the association of hearing impairment and VS-associated tinnitus, the effect of hearing deterioration due to surgery and its relation to the postoperative tinnitus (postTN) is poorly investigated. This knowledge, however, might (i) enlighten the pathophysiology of VS-associated tinnitus (i.e., peripheral or central origin) and (ii) improve preoperative patient counseling. The aim of this study was to understand the predisposition factors for a postTN in relation to hearing outcome after surgery.

Methods: This retrospective study analyzed the presence of tinnitus in 208 patients with unilateral VS before and after surgical removal. A binomial logistic regression was performed to ascertain the effect of pre- and postoperative hearing as well as age, gender, tumor side, and size, and intraoperative cochlear nerve resection (CNR) on the likelihood of postoperative VS-associated tinnitus.

Results: Preoperative tinnitus was the strongest predictor of postTN. In addition, deterioration of functional hearing was increasing, while functional deafferentation (i.e., postoperative hearing loss) of non-functional hearing was reducing the risk of postTN. At the same time, patients with no preoperative tinnitus but complete hearing loss had the lowest risk to suffer from postTN. Patient age, gender, tumor side, and size as well as CNR played a subordinate role.

Conclusion: While the presence of preoperative tinnitus was the strongest predictor of postTN, there is a distinct relationship between hearing outcome and postTN depending on the preoperative situation. Functional or anatomical deafferentation due to surgical tumor removal does not prevent postTN .
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http://dx.doi.org/10.3389/fneur.2018.00136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857542PMC
March 2018

Directional communication during movement execution interferes with tremor in Parkinson's disease.

Mov Disord 2018 02;33(2):251-261

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, and Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen, Tuebingen, Germany.

Background: Both the cerebello-thalamo-cortical circuit and the basal ganglia/cortical motor loop have been postulated to be generators of tremor in PD. The recent suggestion that the basal ganglia trigger tremor episodes and the cerebello-thalamo-cortical circuitry modulates tremor amplitude combines both competing hypotheses. However, the role of the STN in tremor generation and the impact of proprioceptive feedback on tremor suppression during voluntary movements have not been considered in this model yet.

Objectives: The objective of this study was to evaluate the role of the STN and proprioceptive feedback in PD tremor generation during movement execution.

Methods: Local-field potentials of the STN as well as electromyographical and electroencephalographical rhythms were recorded in tremor-dominant and nontremor PD patients while performing voluntary movements of the contralateral hand during DBS surgery. Effective connectivity between these electrophysiological signals were analyzed and compared to electromyographical tremor activity.

Results: There was an intensified information flow between the STN and the muscle in the tremor frequencies (5-8 Hz) for tremor-dominant, in comparison to nontremor, patients. In both subtypes, active movement was associated with an increase of afferent interaction between the muscle and the cortex in the β- and γ-frequencies. The γ-frequency (30-40 Hz) of this communication between muscle and cortex correlated inversely with electromyographical tremor activity.

Conclusions: Our results indicate an involvement of the STN in propagation of tremor-related activity to the muscle. Furthermore, we provide evidence that increased proprioceptive information flow during voluntary movement interferes with central tremor generation. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27221DOI Listing
February 2018

Recruitment of Additional Corticospinal Pathways in the Human Brain with State-Dependent Paired Associative Stimulation.

J Neurosci 2018 02 15;38(6):1396-1407. Epub 2018 Jan 15.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, and

Standard brain stimulation protocols modify human motor cortex excitability by modulating the gain of the activated corticospinal pathways. However, the restoration of motor function following lesions of the corticospinal tract requires also the recruitment of additional neurons to increase the net corticospinal output. For this purpose, we investigated a novel protocol based on brain state-dependent paired associative stimulation.Motor imagery (MI)-related electroencephalography was recorded in healthy males and females for brain state-dependent control of both cortical and peripheral stimulation in a brain-machine interface environment. State-dependency was investigated with concurrent, delayed, and independent stimulation relative to the MI task. Specifically, sensorimotor event-related desynchronization (ERD) in the β-band (16-22 Hz) triggered peripheral stimulation through passive hand opening by a robotic orthosis and transcranial magnetic stimulation to the respective cortical motor representation, either synchronously or subsequently. These MI-related paradigms were compared with paired cortical and peripheral input applied independent of the brain state. Cortical stimulation resulted in a significant increase in corticospinal excitability only when applied brain state-dependently and synchronously to peripheral input. These gains were resistant to a depotentiation task, revealed a nonlinear evolution of plasticity, and were mediated via the recruitment of additional corticospinal neurons rather than via synchronization of neuronal firing. Recruitment of additional corticospinal pathways may be achieved when cortical and peripheral inputs are applied concurrently, and during β-ERD. These findings resemble a gating mechanism and are potentially important for developing closed-loop brain stimulation for the treatment of hand paralysis following lesions of the corticospinal tract. The activity state of the motor system influences the excitability of corticospinal pathways to external input. State-dependent interventions harness this property to increase the connectivity between motor cortex and muscles. These stimulation protocols modulate the gain of the activated pathways, but not the overall corticospinal recruitment. In this study, a brain-machine interface paired peripheral stimulation through passive hand opening with transcranial magnetic stimulation to the respective cortical motor representation during volitional β-band desynchronization. Cortical stimulation resulted in the recruitment of additional corticospinal pathways, but only when applied brain state-dependently and synchronously to peripheral input. These effects resemble a gating mechanism and may be important for the restoration of motor function following lesions of the corticospinal tract.
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http://dx.doi.org/10.1523/JNEUROSCI.2893-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705844PMC
February 2018

Predictors of Preoperative Tinnitus in Unilateral Sporadic Vestibular Schwannoma.

Front Neurol 2017 3;8:378. Epub 2017 Aug 3.

Department of Neurosurgery, Eberhard Karls University, Tuebingen, Germany.

Objective: Nearly two-thirds of patients with vestibular schwannoma (VS) are reporting a significantly impaired quality of life due to tinnitus. VS-associated tinnitus is attributed to an anatomical and physiological damage of the hearing nerve by displacing growth of the tumor. In contrast, the current pathophysiological concept of non-VS tinnitus hypothesizes a maladaptive neuroplasticity of the central nervous system to a (hidden) hearing impairment resulting in a subjective misperception. However, it is unclear whether this concept fits to VS-associated tinnitus. This study aims to determine the clinical predictors of VS-associated tinnitus to ascertain the compatibility of both pathophysiological concepts.

Methods: This retrospective study includes a group of 478 neurosurgical patients with unilateral sporadic VS evaluated preoperatively regarding the occurrence of ipsilateral tinnitus depending on different clinical factors, i.e., age, gender, tumor side, tumor size (T1-T4 according to the Hannover classification), and hearing impairment (Gardner-Robertson classification, GR1-5), using a binary logistic regression.

Results: 61.8% of patients complain about a preoperative tinnitus. The binary logistic regression analysis identified male gender [OR 1.90 (1.25-2.75);  = 0.002] and hearing impairment GR3 [OR 1.90 (1.08-3.35);  = 0.026] and GR4 [OR 8.21 (2.29-29.50);  = 0.001] as positive predictors. In contrast, patients with large T4 tumors [OR 0.33 (0.13-0.86);  = 0.024] and complete hearing loss GR5 [OR 0.36 (0.15-0.84);  = 0.017] were less likely to develop a tinnitus. Yet, 60% of the patients with good clinical hearing (GR1) and 25% of patients with complete hearing loss (GR5) suffered from tinnitus.

Conclusion: These data are good accordance with literature about non-VS tinnitus indicating hearing impairment as main risk factor. In contrast, complete hearing loss appears a negative predictor for tinnitus. For the first time, these findings indicate a non-linear relationship between hearing impairment and tinnitus in unilateral sporadic VS. Our results suggest a similar pathophysiology in VS-associated and non-VS tinnitus.
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http://dx.doi.org/10.3389/fneur.2017.00378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541055PMC
August 2017

Physiological and behavioral effects of β-tACS on brain self-regulation in chronic stroke.

Brain Stimul 2017 Mar - Apr;10(2):251-259. Epub 2016 Nov 9.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, University of Tuebingen, Germany. Electronic address:

Background: Unlike in healthy controls, sensorimotor β-desynchronization (β-ERD) is compromised in stroke patients, i.e., the more severe the patient's motor impairment, the less β-ERD. This, in turn, provides a target substrate for therapeutic brain self-regulation and neurofeedback.

Objective: Transcranial alternating current stimulation (tACS) has been shown to modulate brain oscillations during and after stimulation, and may thus facilitate brain self-regulation during neurofeedback interventions.

Methods: Twenty severely impaired, chronic stroke patients performed kinesthetic motor-imagery while a brain-robot interface transformed β-ERD (17-23 Hz) of the ipsilesional sensorimotor cortex into opening of the paralyzed hand by a robotic orthosis. In a parallel group design, β-tACS (20 Hz, 1.1 mA peak-to-peak amplitude) was applied to the lesioned motor cortex either continuously (c-tACS) before or intermittently (i-tACS) during the intervention. Physiological effects of β-tACS were studied using electroencephalography. The patients' ability for brain self-regulation was captured by neurofeedback performance metrics.

Results: i-tACS - but not c-tACS - improved the classification accuracy of the neurofeedback intervention in comparison to baseline. This effect was mediated via the increased specificity of the classification, i.e., reduced variance of resting oscillations. Neither i-tACS nor c-tACS had aftereffects following the stimulation period.

Conclusion: β-tACS may constitute an adjunct neuromodulation technique during neurofeedback-based interventions for stroke rehabilitation.
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http://dx.doi.org/10.1016/j.brs.2016.11.003DOI Listing
September 2017

Closed-Loop Task Difficulty Adaptation during Virtual Reality Reach-to-Grasp Training Assisted with an Exoskeleton for Stroke Rehabilitation.

Front Neurosci 2016 15;10:518. Epub 2016 Nov 15.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, Eberhard Karls University of Tuebingen Tuebingen, Germany.

Stroke patients with severe motor deficits of the upper extremity may practice rehabilitation exercises with the assistance of a multi-joint exoskeleton. Although this technology enables intensive task-oriented training, it may also lead to slacking when the assistance is too supportive. Preserving the engagement of the patients while providing "assistance-as-needed" during the exercises, therefore remains an ongoing challenge. We applied a commercially available seven degree-of-freedom arm exoskeleton to provide passive gravity compensation during task-oriented training in a virtual environment. During this 4-week pilot study, five severely affected chronic stroke patients performed reach-to-grasp exercises resembling activities of daily living. The subjects received virtual reality feedback from their three-dimensional movements. The level of difficulty for the exercise was adjusted by a performance-dependent real-time adaptation algorithm. The goal of this algorithm was the automated improvement of the range of motion. In the course of 20 training and feedback sessions, this unsupervised adaptive training concept led to a progressive increase of the virtual training space ( < 0.001) in accordance with the subjects' abilities. This learning curve was paralleled by a concurrent improvement of real world kinematic parameters, i.e., range of motion ( = 0.008), accuracy of movement ( = 0.01), and movement velocity ( < 0.001). Notably, these kinematic gains were paralleled by motor improvements such as increased elbow movement ( = 0.001), grip force ( < 0.001), and upper extremity Fugl-Meyer-Assessment score from 14.3 ± 5 to 16.9 ± 6.1 ( = 0.026). Combining gravity-compensating assistance with adaptive closed-loop feedback in virtual reality provides customized rehabilitation environments for severely affected stroke patients. This approach may facilitate motor learning by progressively challenging the subject in accordance with the individual capacity for functional restoration. It might be necessary to apply concurrent restorative interventions to translate these improvements into relevant functional gains of severely motor impaired patients in activities of daily living.
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http://dx.doi.org/10.3389/fnins.2016.00518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108796PMC
November 2016

The role of intraoperative neuromonitoring in adults with Chiari I malformation.

Clin Neurol Neurosurg 2016 Nov 22;150:27-32. Epub 2016 Aug 22.

Department of Neurosurgery, Eberhard-Karls-University of Tuebingen, Tuebingen, Germany.

Object: Suboccipital decompression and duraplasty is considered the treatment of choice for Chiari-I-malformation. Several studies have shown improvement of neurophysiological parameters during decompressive surgery in pediatric patients. However, there is no evidence of the beneficial role of intraoperative neuromonitoring in adults.

Methods: A total of 39 consecutive patients (25 female, age 41.1±14.5 years [mean±SD]) underwent suboccipital decompression for the treatment of symptomatic Chiari-I-malformation senior neurosurgeon and his team. Continuous intraoperative monitoring of somatosensory-evoked potentials of the median nerve (m-SSEPs) and the posterior tibial nerve (t-SSEPs) and motor-evoked potentials to the hand (APB-MEPs) and foot (TA-MEPs) were applied to all patients, alone or in combination. The m-SSEP-N20, t-SSEP-P40, APB-MEP and TA-MEP amplitudes and latencies were recorded at the beginning of the surgery (baseline) and after dura closure. Neurological assessments of the patient were performed prior to surgery, after surgery and during each follow-up visit (3, 6 and 12 months).

Results: There was no significant change in m-SSEP-N20, t-SSEP-P40 or APB-MEP and TA-MEP amplitudes or latencies between the baseline and final measurements (p>0.05, Student's t-test). The average time between both recordings was 125±48min (mean±SD). Postoperatively, none of the patients presented new neurological deficits. During the mean follow-up period of 22.4±20.3 months, 92.6% of the symptoms improved or remained stable. Three patients (8.1%) exhibited a relapse of symptoms after 25.7±7.6 months, and only one patient (2.5%) needed secondary decompression after 24 months.

Conclusion: Intraoperative neuromonitoring (INM) during the primary treatment of Chiari-I-malformation shows only subtle non-significant changes in SSEPs/MEPs without clinical correlation during suboccipital decompression. INM is not considered a prerequisite for a safe suboccipital decompression when operated by an experienced surgical team.
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http://dx.doi.org/10.1016/j.clineuro.2016.08.019DOI Listing
November 2016

Hybrid Neuroprosthesis for the Upper Limb: Combining Brain-Controlled Neuromuscular Stimulation with a Multi-Joint Arm Exoskeleton.

Front Neurosci 2016 9;10:367. Epub 2016 Aug 9.

Division of Functional and Restorative Neurosurgery, Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen Tuebingen, Germany.

Brain-machine interface-controlled (BMI) neurofeedback training aims to modulate cortical physiology and is applied during neurorehabilitation to increase the responsiveness of the brain to subsequent physiotherapy. In a parallel line of research, robotic exoskeletons are used in goal-oriented rehabilitation exercises for patients with severe motor impairment to extend their range of motion (ROM) and the intensity of training. Furthermore, neuromuscular electrical stimulation (NMES) is applied in neurologically impaired patients to restore muscle strength by closing the sensorimotor loop. In this proof-of-principle study, we explored an integrated approach for providing assistance as needed to amplify the task-related ROM and the movement-related brain modulation during rehabilitation exercises of severely impaired patients. For this purpose, we combined these three approaches (BMI, NMES, and exoskeleton) in an integrated neuroprosthesis and studied the feasibility of this device in seven severely affected chronic stroke patients who performed wrist flexion and extension exercises while receiving feedback via a virtual environment. They were assisted by a gravity-compensating, seven degree-of-freedom exoskeleton which was attached to the paretic arm. NMES was applied to the wrist extensor and flexor muscles during the exercises and was controlled by a hybrid BMI based on both sensorimotor cortical desynchronization (ERD) and electromyography (EMG) activity. The stimulation intensity was individualized for each targeted muscle and remained subthreshold, i.e., induced no overt support. The hybrid BMI controlled the stimulation significantly better than the offline analyzed ERD (p = 0.028) or EMG (p = 0.021) modality alone. Neuromuscular stimulation could be well integrated into the exoskeleton-based training and amplified both the task-related ROM (p = 0.009) and the movement-related brain modulation (p = 0.019). Combining a hybrid BMI with neuromuscular stimulation and antigravity assistance augments upper limb function and brain activity during rehabilitation exercises and may thus provide a novel restorative framework for severely affected stroke patients.
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http://dx.doi.org/10.3389/fnins.2016.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977295PMC
August 2016

Compensation or Restoration: Closed-Loop Feedback of Movement Quality for Assisted Reach-to-Grasp Exercises with a Multi-Joint Arm Exoskeleton.

Front Neurosci 2016 21;10:280. Epub 2016 Jun 21.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen, Germany.

Assistive technology allows for intensive practice and kinematic measurements during rehabilitation exercises. More recent approaches attach a gravity-compensating multi-joint exoskeleton to the upper extremity to facilitate task-oriented training in three-dimensional space with virtual reality feedback. The movement quality, however, is mostly captured through end-point measures that lack information on proximal inter-joint coordination. This limits the differentiation between compensation strategies and genuine restoration both during the exercise and in the course of rehabilitation. We extended in this proof-of-concept study a commercially available seven degree-of-freedom arm exoskeleton by using the real-time sensor data to display a three-dimensional multi-joint visualization of the user's arm. Ten healthy subjects and three severely affected chronic stroke patients performed reach-to-grasp exercises resembling activities of daily living assisted by the attached exoskeleton and received closed-loop online feedback of the three-dimensional movement in virtual reality. Patients in this pilot study differed significantly with regard to motor performance (accuracy, temporal efficiency, range of motion) and movement quality (proximal inter-joint coordination) from the healthy control group. In the course of 20 training and feedback sessions over 4 weeks, these pathological measures improved significantly toward the reference parameters of healthy participants. It was moreover feasible to capture the evolution of movement pattern kinematics of the shoulder and elbow and to quantify the individual degree of natural movement restoration for each patient. The virtual reality visualization and closed-loop feedback of joint-specific movement kinematics makes it possible to detect compensation strategies and may provide a tool to achieve the rehabilitation goals in accordance with the individual capacity for genuine functional restoration; a proposal that warrants further investigation in controlled studies with a larger cohort of stroke patients.
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http://dx.doi.org/10.3389/fnins.2016.00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914560PMC
July 2016

Detecting a Cortical Fingerprint of Parkinson's Disease for Closed-Loop Neuromodulation.

Front Neurosci 2016 30;10:110. Epub 2016 Mar 30.

Division of Functional and Restorative Neurosurgery and Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen Tuebingen, Germany.

Recent evidence suggests that deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) mediates its clinical effects by modulating cortical oscillatory activity, presumably via a direct cortico-subthalamic connection. This observation might pave the way for novel closed-loop approaches comprising a cortical sensor. Enhanced beta oscillations (13-35 Hz) have been linked to the pathophysiology of PD and may serve as such a candidate marker to localize a cortical area reliably modulated by DBS. However, beta-oscillations are widely distributed over the cortical surface, necessitating an additional signal source for spotting the cortical area linked to the pathologically synchronized cortico-subcortical motor network. In this context, both cortico-subthalamic coherence and cortico-muscular coherence (CMC) have been studied in PD patients. Whereas, the former requires invasive recordings, the latter allows for non-invasive detection, but displays a rather distributed cortical synchronization pattern in motor tasks. This distributed cortical representation may conflict with the goal of detecting a cortical localization with robust biomarker properties which is detectable on a single subject basis. We propose that this limitation could be overcome when recording CMC at rest. We hypothesized that-unlike healthy subjects-PD would show CMC at rest owing to the enhanced beta oscillations observed in PD. By performing source space analysis of beta CMC recorded during resting-state magnetoencephalography, we provide preliminary evidence in one patient for a cortical hot spot that is modulated most strongly by subthalamic DBS. Such a spot would provide a prominent target region either for direct neuromodulation or for placing a potential sensor in closed-loop DBS approaches, a proposal that requires investigation in a larger cohort of PD patients.
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http://dx.doi.org/10.3389/fnins.2016.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811963PMC
April 2016

Brain State-Dependent Transcranial Magnetic Closed-Loop Stimulation Controlled by Sensorimotor Desynchronization Induces Robust Increase of Corticospinal Excitability.

Brain Stimul 2016 May-Jun;9(3):415-424. Epub 2016 Feb 16.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, Eberhard Karls University, Tuebingen, Germany. Electronic address:

Background: Desynchronization of sensorimotor rhythmic activity increases instantaneous corticospinal excitability, as indexed by amplitudes of motor-evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS). The accumulative effect of cortical stimulation in conjunction with sensorimotor desynchronization is, however, unclear.

Objective: The aim of this study was to investigate the effects of repetitive pairing event-related desynchronization (ERD) with TMS of the precentral gyrus on corticospinal excitability.

Methods: Closed-loop single-pulse TMS was controlled by beta-band (16-22 Hz) ERD during motor-imagery of finger extension and applied within a brain-computer interface environment in eleven healthy subjects. The same number and pattern of stimuli were applied in a control group of eleven subjects during rest, i.e. independent of ERD. To probe for plasticity resistant to depotentiation, stimulation protocols were followed by a depotentiation task.

Results: Brain state-dependent application of approximately 300 TMS pulses during beta-ERD resulted in a significant increase of corticospinal excitability. By contrast, the identical stimulation pattern applied independent of beta-ERD in the control experiment resulted in a decrease of corticospinal excitability. These effects persisted beyond the period of stimulation and the depotentiation task.

Conclusion: These results could be instrumental in developing new therapeutic approaches such as the application of closed-loop stimulation in the context of neurorehabilitation.
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http://dx.doi.org/10.1016/j.brs.2016.02.007DOI Listing
September 2017

Enhanced motor learning with bilateral transcranial direct current stimulation: Impact of polarity or current flow direction?

Clin Neurophysiol 2016 Apr 12;127(4):2119-26. Epub 2016 Jan 12.

Division of Functional and Restorative Neurosurgery, and Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen, Germany. Electronic address:

Objective: Bilateral transcranial direct current stimulation (TDCS) is superior to unilateral TDCS when targeting motor learning. This effect could be related to either the current flow direction or additive polarity-specific effects on each hemisphere.

Methods: This sham-controlled randomized study included fifty right-handed healthy subjects in a parallel-group design who performed an exoskeleton-based motor task of the proximal left arm on three consecutive days. Prior to training, we applied either sham, right anodal (a-TDCS), left cathodal (c-TDCS), concurrent a-TDCS and c-TDCS with two independent current sources and return electrodes (double source (ds)-TDCS) or classical bilateral stimulation (bi-TDCS).

Results: Motor performance improved over time for both unilateral (a-TDCS, c-TDCS) and bilateral (bi-TDCS, ds-TDCS) TDCS montages. However, only the two bilateral paradigms led to an improvement of the final motor performance at the end of the training period as compared to the sham condition. There was no difference between the two bilateral stimulation conditions (bi-TDCS, ds-TDCS).

Conclusion: Bilateral TDCS is more effective than unilateral stimulation due to its polarity-specific effects on each hemisphere rather than due to its current flow direction.

Significance: This study is the first systematic evaluation of stimulation polarity and current flow direction of bi-hemispheric motor cortex TDCS on motor learning of proximal upper limb muscles.
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http://dx.doi.org/10.1016/j.clinph.2015.12.020DOI Listing
April 2016

An Unsupervised Online Spike-Sorting Framework.

Int J Neural Syst 2016 Aug 27;26(5):1550042. Epub 2015 Oct 27.

* Division of Functional and Restorative Neurosurgery & Division of Translational Neurosurgery, Department of Neurosurgery, and Neuroprosthetics Research Group, Werner Reichardt Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen, Otfried-Mueller-Str.45, 72076 Tuebingen, Germany.

Extracellular neuronal microelectrode recordings can include action potentials from multiple neurons. To separate spikes from different neurons, they can be sorted according to their shape, a procedure referred to as spike-sorting. Several algorithms have been reported to solve this task. However, when clustering outcomes are unsatisfactory, most of them are difficult to adjust to achieve the desired results. We present an online spike-sorting framework that uses feature normalization and weighting to maximize the distinctiveness between different spike shapes. Furthermore, multiple criteria are applied to either facilitate or prevent cluster fusion, thereby enabling experimenters to fine-tune the sorting process. We compare our method to established unsupervised offline (Wave_Clus (WC)) and online (OSort (OS)) algorithms by examining their performance in sorting various test datasets using two different scoring systems (AMI and the Adamos metric). Furthermore, we evaluate sorting capabilities on intra-operative recordings using established quality metrics. Compared to WC and OS, our algorithm achieved comparable or higher scores on average and produced more convincing sorting results for intra-operative datasets. Thus, the presented framework is suitable for both online and offline analysis and could substantially improve the quality of microelectrode-based data evaluation for research and clinical application.
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http://dx.doi.org/10.1142/S0129065715500422DOI Listing
August 2016

Brain-robot interface driven plasticity: Distributed modulation of corticospinal excitability.

Neuroimage 2016 Jan 24;125:522-532. Epub 2015 Oct 24.

Division of Functional and Restorative Neurosurgery & Division of Translational Neurosurgery, Department of Neurosurgery, Eberhard Karls University Tuebingen, Germany; Neuroprosthetics Research Group, Werner Reichardt Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen, Germany. Electronic address:

Brain-robot interfaces (BRI) are studied as novel interventions to facilitate functional restoration in patients with severe and persistent motor deficits following stroke. They bridge the impaired connection in the sensorimotor loop by providing brain-state dependent proprioceptive feedback with orthotic devices attached to the hand or arm of the patients. The underlying neurophysiology of this BRI neuromodulation is still largely unknown. We investigated changes of corticospinal excitability with transcranial magnetic stimulation in thirteen right-handed healthy subjects who performed 40min of kinesthetic motor imagery receiving proprioceptive feedback with a robotic orthosis attached to the left hand contingent to event-related desynchronization of the right sensorimotor cortex in the β-band (16-22Hz). Neural correlates of this BRI intervention were probed by acquiring the stimulus-response curve (SRC) of both motor evoked potential (MEP) peak-to-peak amplitudes and areas under the curve. In addition, a motor mapping was obtained. The specificity of the effects was studied by comparing two neighboring hand muscles, one BRI-trained and one control muscle. Robust changes of MEP amplitude but not MEP area occurred following the BRI intervention, but only in the BRI-trained muscle. The steep part of the SRC showed an MEP increase, while the plateau of the SRC showed an MEP decrease. MEP mapping revealed a distributed pattern with a decrease of excitability in the hand area of the primary motor cortex, which controlled the BRI, but an increase of excitability in the surrounding somatosensory and premotor cortex. In conclusion, the BRI intervention induced a complex pattern of modulated corticospinal excitability, which may boost subsequent motor learning during physiotherapy.
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http://dx.doi.org/10.1016/j.neuroimage.2015.09.074DOI Listing
January 2016

Reinforcement learning of self-regulated β-oscillations for motor restoration in chronic stroke.

Front Hum Neurosci 2015 3;9:391. Epub 2015 Jul 3.

Division of Functional and Restorative Neurosurgery and Division of Translational Neurosurgery, Department of Neurosurgery, Eberhard Karls University Tuebingen Tuebingen, Germany ; Neuroprosthetics Research Group, Werner Reichardt Centre for Integrative Neuroscience, Eberhard Karls University Tuebingen Tuebingen, Germany.

Neurofeedback training of Motor imagery (MI)-related brain-states with brain-computer/brain-machine interfaces (BCI/BMI) is currently being explored as an experimental intervention prior to standard physiotherapy to improve the motor outcome of stroke rehabilitation. The use of BCI/BMI technology increases the adherence to MI training more efficiently than interventions with sham or no feedback. Moreover, pilot studies suggest that such a priming intervention before physiotherapy might-like some brain stimulation techniques-increase the responsiveness of the brain to the subsequent physiotherapy, thereby improving the general clinical outcome. However, there is little evidence up to now that these BCI/BMI-based interventions have achieved operate conditioning of specific brain states that facilitate task-specific functional gains beyond the practice of primed physiotherapy. In this context, we argue that BCI/BMI technology provides a valuable neurofeedback tool for rehabilitation but needs to aim at physiological features relevant for the targeted behavioral gain. Moreover, this therapeutic intervention has to be informed by concepts of reinforcement learning to develop its full potential. Such a refined neurofeedback approach would need to address the following issues: (1) Defining a physiological feedback target specific to the intended behavioral gain, e.g., β-band oscillations for cortico-muscular communication. This targeted brain state could well be different from the brain state optimal for the neurofeedback task, e.g., α-band oscillations for differentiating MI from rest; (2) Selecting a BCI/BMI classification and thresholding approach on the basis of learning principles, i.e., balancing challenge and reward of the neurofeedback task instead of maximizing the classification accuracy of the difficulty level device; and (3) Adjusting the difficulty level in the course of the training period to account for the cognitive load and the learning experience of the participant. Here, we propose a comprehensive neurofeedback strategy for motor restoration after stroke that addresses these aspects, and provide evidence for the feasibility of the suggested approach by demonstrating that dynamic threshold adaptation based on reinforcement learning may lead to frequency-specific operant conditioning of β-band oscillations paralleled by task-specific motor improvement; a proposal that requires investigation in a larger cohort of stroke patients.
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http://dx.doi.org/10.3389/fnhum.2015.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490244PMC
July 2015

Blurring the boundaries between frame-based and frameless stereotaxy: feasibility study for brain biopsies performed with the use of a head-mounted robot.

J Neurosurg 2015 Sep 12;123(3):737-42. Epub 2015 Jun 12.

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, Eberhard Karls University, Tuebingen; and.

Object: Frame-based stereotactic interventions are considered the gold standard for brain biopsies, but they have limitations with regard to flexibility and patient comfort because of the bulky head ring attached to the patient. Frameless image guidance systems that use scalp fiducial markers offer more flexibility and patient comfort but provide less stability and accuracy during drilling and biopsy needle positioning. Head-mounted robot-guided biopsies could provide the advantages of these 2 techniques without the downsides. The goal of this study was to evaluate the feasibility and safety of a robotic guidance device, affixed to the patient's skull through a small mounting platform, for use in brain biopsy procedures.

Methods: This was a retrospective study of 37 consecutive patients who presented with supratentorial lesions and underwent brain biopsy procedures in which a surgical guidance robot was used to determine clinical outcomes and technical procedural operability.

Results: The portable head-mounted device was well tolerated by the patients and enabled stable drilling and needle positioning during surgery. Flexible adjustments of predefined paths and selection of new trajectories were successfully performed intraoperatively without the need for manual settings and fixations. The patients experienced no permanent deficits or infections after surgery.

Conclusions: The head-mounted robot-guided approach presented here combines the stability of a bone-mounted set-up with the flexibility and tolerability of frameless systems. By reducing human interference (i.e., manual parameter settings, calibrations, and adjustments), this technology might be particularly useful in neurosurgical interventions that necessitate multiple trajectories.
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http://dx.doi.org/10.3171/2014.12.JNS141781DOI Listing
September 2015